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101. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Subjects
Authorship, Periodicals as Topic
Published
2020
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102. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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103. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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104. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Subjects
Publishing, Editorial Policies
Published
2020
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105. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Subjects
Authorship, COVID-19, Humans, Pandemics, Peer Review, Research, Research Personnel, SARS-CoV-2, Social Isolation, Betacoronavirus, Coronavirus Infections ethnology, Pneumonia, Viral ethnology, Publishing supply & distribution
Published
2020
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106. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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107. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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108. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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109. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Subjects
Humans, Editorial Policies, Publishing
Published
2020
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110. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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111. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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112. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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113. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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114. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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115. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Subjects
Authorship standards, Peer Review standards, Editorial Policies, Periodicals as Topic standards
Published
2020
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116. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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117. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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118. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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119. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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120. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Subjects
Biochemistry, Periodicals as Topic
Published
2020
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121. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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122. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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123. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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124. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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125. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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126. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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127. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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128. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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129. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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130. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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131. Update to Our Reader, Reviewer, and Author Communities-April 2020.

Author

Burrows CJ, Wang S, Kim HJ, Meyer GJ, Schanze K, Lee TR, Lutkenhaus JL, Kaplan D, Jones C, Bertozzi C, Kiessling L, Mulcahy MB, Lindsley CW, Finn MG, Blum JD, Kamat P, Aldrich CC, Rowan S, Bin Liu, Liotta D, Weiss PS, Zhang D, Ganesh KN, Sexton P, Atwater HA, Gooding JJ, Allen DT, Voigt CA, Sweedler J, Schepartz A, Rotello V, Lecommandoux S, Sturla SJ, Hammes-Schiffer S, Buriak J, Steed JW, Wu H, Zimmerman J, Brooks B, Savage P, Tolman W, Hofmann TF, Brennecke JF, Holme TA, Merz KM Jr, Scuseria G, Jorgensen W, Georg GI, Wang S, Proteau P, Yates JR 3rd, Stang P, Walker GC, Hillmyer M, Taylor LS, Odom TW, Carreira E, Rossen K, Chirik P, Miller SJ, McCoy A, Shea JE, Zanni M, Murphy C, Scholes G, and Loo JA

Published
2020
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132. Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome.

Author

Rožman K, Alexander EM, Ogorevc E, Bozovičar K, Sosič I, Aldrich CC, and Gobec S

Subjects
Ficusin chemistry, Humans, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis pathogenicity, Proteasome Inhibitors chemistry, Proteolysis drug effects, Tuberculosis microbiology, Ubiquitin chemistry, Ubiquitins chemistry, Ficusin pharmacology, Proteasome Inhibitors pharmacology, Tuberculosis drug therapy
Abstract

Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the Mycobacterium tuberculosis proteasome in low micromolar concentrations. The best inhibitors, i.e., 8 , 11 , 13 and 15 , exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. N -(cyanomethyl)acetamide 8 ( K i = 5.6 µM) and carboxaldehyde-based derivative 15 ( K i = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters 11 and 13 irreversibly inhibited the enzyme with K i values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, PR-957 , is a noncompetitive irreversible inhibitor of the mycobacterial proteasome ( K i = 5.2 ± 1.9 µM, k inact / K i = 96 ± 41 M -1 ·s -1 ). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis.

Published
2020
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133. The Biotin Biosynthetic Pathway in Mycobacterium tuberculosis is a Validated Target for the Development of Antibacterial Agents.

Author

Bockman MR, Mishra N, and Aldrich CC

Subjects
Animals, Antitubercular Agents, Biosynthetic Pathways, Biotin, Humans, Mycobacterium tuberculosis, Tuberculosis
Abstract

Mycobacterium tuberculosis, responsible for Tuberculosis (TB), remains the leading cause of mortality among infectious diseases worldwide from a single infectious agent, with an estimated 1.7 million deaths in 2016. Biotin is an essential cofactor in M. tuberculosis that is required for lipid biosynthesis and gluconeogenesis. M. tuberculosis relies on de novo biotin biosynthesis to obtain this vital cofactor since it cannot scavenge sufficient biotin from a mammalian host. The biotin biosynthetic pathway in M. tuberculosis has been well studied and rigorously genetically validated providing a solid foundation for medicinal chemistry efforts. This review examines the mechanism and structure of the enzymes involved in biotin biosynthesis and ligation, summarizes the reported genetic validation studies of the pathway, and then analyzes the most promising inhibitors and natural products obtained from structure-based drug design and phenotypic screening., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Published
2020
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135. Macozinone: revised synthesis and crystal structure of a promising new drug for treating drug-sensitive and drug-resistant tuberculosis.

Author

Zhang G and Aldrich CC

Subjects
Antitubercular Agents chemical synthesis, Crystallography, X-Ray, Drug Resistance, Bacterial, Hydrogen Bonding, Molecular Conformation, Piperazines chemical synthesis, Thiazines chemical synthesis, Tuberculosis, Pulmonary drug therapy, Antitubercular Agents chemistry, Piperazines chemistry, Thiazines chemistry
Abstract

Mycobacterium tuberculosis (Mtb), the principal etiological agent of tuberculosis (TB), infects over one-quarter of humanity and is now the leading cause of infectious disease mortality by a single pathogen. Macozinone {2-[4-(cyclohexylmethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, C 20 H 23 F 3 N 4 O 3 S} is a promising new drug for treating drug-sensitive and drug-resistant TB that has successfully completed phase I clinical trials. We report the complete spectroscopic and structural characterization by 1 H NMR, 13 C NMR, HRMS, IR, and X-ray crystallography. The cyclohexyl moiety is observed to be nearly perpendicular to the core formed by the 1,3-benzothiazin-4-one and piperazine groups. The central piperazine ring adopts a slightly distorted chair conformation caused by sp 2 -hybridization of the nitro N atom, which donates into the electron-deficient 1,3-benzothiazin-4-one group.

Published
2019
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136. Noncompetitive inhibitors of TNFR1 probe conformational activation states.

Author

Lo CH, Schaaf TM, Grant BD, Lim CK, Bawaskar P, Aldrich CC, Thomas DD, and Sachs JN

Subjects
HEK293 Cells, Humans, Protein Domains, Protein Structure, Quaternary, Protein Multimerization, Receptors, Tumor Necrosis Factor, Type I antagonists & inhibitors, Receptors, Tumor Necrosis Factor, Type I chemistry
Abstract

Tumor necrosis factor receptor 1 (TNFR1) is a central mediator of the inflammatory pathway and is associated with several autoimmune diseases such as rheumatoid arthritis. A revision to the canonical model of TNFR1 activation suggests that activation involves conformational rearrangements of preassembled receptor dimers. Here, we identified small-molecule allosteric inhibitors of TNFR1 activation and probed receptor dimerization and function. Specifically, we used a fluorescence lifetime-based high-throughput screen and biochemical, biophysical, and cellular assays to identify small molecules that noncompetitively inhibited the receptor without reducing ligand affinity or disrupting receptor dimerization. We also found that residues in the ligand-binding loop that are critical to the dynamic coupling between the extracellular and the transmembrane domains played a key gatekeeper role in the conformational dynamics associated with signal propagation. Last, using a simple structure-activity relationship analysis, we demonstrated that these newly found molecules could be further optimized for improved potency and specificity. Together, these data solidify and deepen the new model for TNFR1 activation., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Published
2019
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137. Mechanism of a Standalone β-Lactone Synthetase: New Continuous Assay for a Widespread ANL Superfamily Enzyme.

Author

Robinson SL, Christenson JK, Richman JE, Jenkins DJ, Neres J, Fonseca DR, Aldrich CC, and Wackett LP

Subjects
Adenosine Triphosphate metabolism, Amino Acid Sequence, Carbon-Oxygen Lyases genetics, Catalysis, Catalytic Domain genetics, Enzyme Assays methods, Hydroxy Acids metabolism, Kinetics, Magnesium metabolism, Models, Chemical, Mutagenesis, Site-Directed, Phylogeny, Protein Binding, Sequence Alignment, Substrate Specificity, Xanthomonas campestris enzymology, Carbon-Oxygen Lyases chemistry, Carbon-Oxygen Lyases metabolism
Abstract

Enzyme-catalyzed β-lactone formation from β-hydroxy acids is a crucial step in bacterial biosynthesis of β-lactone natural products and membrane hydrocarbons. We developed a novel, continuous assay for β-lactone synthetase activity using synthetic β-hydroxy acid substrates with alkene or alkyne moieties. β-Lactone formation is followed by rapid decarboxylation to form a conjugated triene chromophore for real-time evaluation by UV/Vis spectroscopy. The assay was used to determine steady-state kinetics of a long-chain β-lactone synthetase, OleC, from the plant pathogen Xanthomonas campestris. Site-directed mutagenesis was used to test the involvement of conserved active site residues in Mg 2+ and ATP binding. A previous report suggested OleC adenylated the substrate hydroxy group. Here we present several lines of evidence, including hydroxylamine trapping of the AMP intermediate, to demonstrate the substrate carboxyl group is adenylated prior to making the β-lactone final product. A panel of nine substrate analogues were used to investigate the substrate specificity of X. campestris OleC by HPLC and GC-MS. Stereoisomers of 2-hexyl-3hydroxyoctanoic acid were synthesized and OleC preferred the (2R,3S) diastereomer consistent with the stereo-preference of upstream and downstream pathway enzymes. This biochemical knowledge was used to guide phylogenetic analysis of the β-lactone synthetases to map their functional diversity within the acyl-CoA synthetase, NRPS adenylation domain, and luciferase superfamily., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2019
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138. Development of an imidazole salt catalytic system for the preparation of bis(indolyl)methanes and bis(naphthyl)methane.

Author

Wang X and Aldrich CC

Subjects
Catalysis, Proton Magnetic Resonance Spectroscopy, Imidazoles chemistry, Methane chemistry, Salts chemistry
Abstract

Imidazolium salts are shown to catalyze the rapid room temperature reaction of indoles or naphthol with aldehydes to provide bis(indolyl)methanes or bis(naphthol)methane in excellent yields and the reaction proceeds optimally in dichloromethane with no base additives. The reaction exhibits a broad substrate tolerance and occurs through nucleophilic activation of the indoles and naphthols through a cation-π interaction., Competing Interests: The authors have declared that no competing interests exist.

Published
2019
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139. Investigation of ( S)-(-)-Acidomycin: A Selective Antimycobacterial Natural Product That Inhibits Biotin Synthase.

Author

Bockman MR, Engelhart CA, Cramer JD, Howe MD, Mishra NK, Zimmerman M, Larson P, Alvarez-Cabrera N, Park SW, Boshoff HIM, Bean JM, Young VG Jr, Ferguson DM, Dartois V, Jarrett JT, Schnappinger D, and Aldrich CC

Subjects
Animals, Antitubercular Agents chemical synthesis, Antitubercular Agents chemistry, Bacterial Proteins chemistry, Bacterial Proteins genetics, Bacterial Proteins metabolism, Biological Products chemical synthesis, Biological Products chemistry, Biological Products pharmacology, Biotin biosynthesis, Caproates chemical synthesis, Caproates chemistry, Caproates pharmacology, Drug Resistance, Bacterial, Humans, Kinetics, Mice, Microbial Sensitivity Tests, Mycobacterium tuberculosis chemistry, Mycobacterium tuberculosis genetics, Sulfurtransferases chemistry, Sulfurtransferases genetics, Sulfurtransferases metabolism, Thiazolidines chemical synthesis, Thiazolidines chemistry, Tuberculosis drug therapy, Antitubercular Agents pharmacology, Bacterial Proteins antagonists & inhibitors, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis enzymology, Sulfurtransferases antagonists & inhibitors, Thiazolidines pharmacology, Tuberculosis microbiology
Abstract

The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of ( S)-(-)-acidomycin are described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (minimum inhibitory concentrations (MICs) = 0.096-6.2 μM) but is inactive against nontuberculosis mycobacteria and Gram-positive and Gram-negative pathogens (MICs > 1000 μM). Complementation studies with biotin biosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits biotin synthesis with a K i of approximately 1 μM through the competitive inhibition of biotin synthase (BioB) and also stimulates unproductive cleavage of S-adenosyl-l-methionine (SAM) to generate the toxic metabolite 5'-deoxyadenosine. Cell studies demonstrate acidomycin selectively accumulates in M. tuberculosis providing a mechanistic basis for the observed antibacterial activity. The development of spontaneous resistance by M. tuberculosis to acidomycin was difficult, and only low-level resistance to acidomycin was observed by overexpression of BioB. Collectively, the results provide a foundation to advance acidomycin and highlight BioB as a promising target.

Published
2019
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140. A Cinchona Alkaloid Antibiotic That Appears To Target ATP Synthase in Streptococcus pneumoniae.

Author

Wang X, Zeng Y, Sheng L, Larson P, Liu X, Zou X, Wang S, Guo K, Ma C, Zhang G, Cui H, Ferguson DM, Li Y, Zhang J, and Aldrich CC

Subjects
Anti-Bacterial Agents chemistry, Anti-Bacterial Agents metabolism, Binding Sites, Cinchona Alkaloids chemistry, Cinchona Alkaloids metabolism, Drug Resistance, Microbial, Microbial Sensitivity Tests, Mitochondrial Proton-Translocating ATPases metabolism, Structure-Activity Relationship, Anti-Bacterial Agents pharmacology, Cinchona Alkaloids pharmacology, Mitochondrial Proton-Translocating ATPases antagonists & inhibitors, Streptococcus pneumoniae enzymology
Abstract

Optochin, a cinchona alkaloid derivative discovered over 100 years ago, possesses highly selective antibacterial activity toward Streptococcus pneumoniae. Pneumococcal disease remains the leading source of bacterial pneumonia and meningitis worldwide. The structure-activity relationships of optochin were examined through modification to both the quinoline and quinuclidine subunits, which led to the identification of analogue 48 with substantially improved activity. Resistance and molecular modeling studies indicate that 48 likely binds to the c-ring of ATP synthase near the conserved glutamate 52 ion-binding site, while mechanistic studies demonstrated that 48 causes cytoplasmic acidification. Initial pharmacokinetic and drug metabolism analyses of optochin and 48 revealed limitations of these quinine analogues, which were rapidly cleared, resulting in poor in vivo exposure through hydroxylation pendants to the quinuclidine and O-dealkylation of the quinoline. Collectively, the results provide a foundation to advance 48 and highlight ATP synthase as a promising target for antibiotic development.

Published
2019
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141. Spirocyclic and Bicyclic 8-Nitrobenzothiazinones for Tuberculosis with Improved Physicochemical and Pharmacokinetic Properties.

Author

Zhang G, Howe M, and Aldrich CC

Abstract

8-Nitrobenzothiazinones (BTZs) typified by the second-generation analogue PBTZ169 are a new class of antitubercular agents. The activity of BTZs and lipophilicity are tightly coupled since the molecular target DprE1 is located in the mycobacterial cell envelope. A series of analogues was designed to address the notorious insolubility of the BTZs while preserving the required lipophilicity. This was accomplished by decreasing the molecular planarity and symmetry through bioisosteric replacement of the piperazine moiety of PBTZ169 with spirocyclic and bicyclic diamines. Several promising compounds with improved aqueous solubilities were identified with potent antitubercular activity. Compound 5 was identified as the most promising candidate based on its excellent antitubercular activity (MIC of 32 nM), more than 1000-fold improvement in solubility, 2-fold lower clearance in mouse and human microsomes relative to PBTZ169, and promising pharmacokinetic parameters., Competing Interests: The authors declare no competing financial interest.

Published
2019
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142. Structural Basis of Polyketide Synthase O-Methylation.

Author

Skiba MA, Bivins MM, Schultz JR, Bernard SM, Fiers WD, Dan Q, Kulkarni S, Wipf P, Gerwick WH, Sherman DH, Aldrich CC, and Smith JL

Subjects
Bacterial Proteins chemistry, Bacterial Proteins genetics, Catalytic Domain genetics, Cyanobacteria enzymology, Methylation, Methyltransferases genetics, Mutagenesis, Site-Directed, Mutation, Myxococcales enzymology, Polyketide Synthases genetics, Protein Conformation, Protein Domains, Substrate Specificity, Methyltransferases chemistry, Polyketide Synthases chemistry, Polyketides chemical synthesis
Abstract

Modular type I polyketide synthases (PKSs) produce some of the most chemically complex metabolites in nature through a series of multienzyme modules. Each module contains a variety of catalytic domains to selectively tailor the growing molecule. PKS O-methyltransferases ( O-MTs) are predicted to methylate β-hydroxyl or β-keto groups, but their activity and structure have not been reported. We determined the domain boundaries and characterized the catalytic activity and structure of the StiD and StiE O-MTs, which methylate opposite β-hydroxyl stereocenters in the myxobacterial stigmatellin biosynthetic pathway. Substrate stereospecificity was demonstrated for the StiD O-MT. Key catalytic residues were identified in the crystal structures and investigated in StiE O-MT via site-directed mutagenesis and further validated with the cyanobacterial CurL O-MT from the curacin biosynthetic pathway. Initial structural and biochemical analysis of PKS O-MTs supplies a new chemoenzymatic tool, with the unique ability to selectively modify hydroxyl groups during polyketide biosynthesis.

Published
2018
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143. Trapping interactions between catalytic domains and carrier proteins of modular biosynthetic enzymes with chemical probes.

Author

Gulick AM and Aldrich CC

Subjects
Acetamides chemistry, Biological Products metabolism, Catalytic Domain, Crystallography, X-Ray, Enzymes chemistry, Peptide Synthases chemistry, Peptide Synthases metabolism, Polyketide Synthases chemistry, Polyketide Synthases metabolism, Protein Domains, Protein Interaction Maps physiology, Proteomics methods, Biochemistry methods, Carrier Proteins chemistry, Carrier Proteins metabolism, Enzymes metabolism, Molecular Probes chemistry
Abstract

Covering: up to early 2018 The Nonribosomal Peptide Synthetases (NRPSs) and Polyketide Synthases (PKSs) are families of modular enzymes that produce a tremendous diversity of natural products, with antibacterial, antifungal, immunosuppressive, and anticancer activities. Both enzymes utilize a fascinating modular architecture in which the synthetic intermediates are covalently attached to a peptidyl- or acyl-carrier protein that is delivered to catalytic domains for natural product elongation, modification, and termination. An investigation of the structural mechanism therefore requires trapping the often transient interactions between the carrier and catalytic domains. Many novel chemical probes have been produced to enable the structural and functional investigation of multidomain NRPS and PKS structures. This review will describe the design and implementation of the chemical tools that have proven to be useful in biochemical and biophysical studies of these natural product biosynthetic enzymes.

Published
2018
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144. Methionine Antagonizes para -Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis .

Author

Howe MD, Kordus SL, Cole MS, Bauman AA, Aldrich CC, Baughn AD, and Minato Y

Subjects
4-Aminobenzoic Acid metabolism, 4-Aminobenzoic Acid pharmacology, Bacterial Proteins metabolism, Biotin metabolism, Drug Resistance, Bacterial genetics, Folic Acid pharmacology, Methionine metabolism, Microbial Sensitivity Tests, Mycobacterium drug effects, Mycobacterium genetics, Mycobacterium growth & development, Mycobacterium tuberculosis growth & development, Aminosalicylic Acid pharmacology, Antitubercular Agents pharmacology, Drug Antagonism, Methionine pharmacology, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis metabolism
Abstract

para -Aminosalicylic acid (PAS) is a second-line anti-tubercular drug that is used for the treatment of drug-resistant tuberculosis (TB). PAS efficacy in the treatment of TB is limited by its lower potency against Mycobacterium tuberculosis relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, para -aminobenzoic acid (PABA) and methionine, antagonize PAS and structurally related anti-folate drugs. While the basis for PABA-mediated antagonism of anti-folates is understood, the mechanism for methionine-based antagonism remains undefined. In the present study, we used both targeted and untargeted approaches to identify factors associated with methionine-mediated antagonism of PAS activity. We found that synthesis of folate precursors as well as a putative amino acid transporter, designated MetM, play crucial roles in this process. Disruption of metM by transposon insertion resulted in a ≥30-fold decrease in uptake of methionine in M. bovis BCG, indicating that metM is the major facilitator of methionine transport. We also discovered that intracellular biotin confers intrinsic PAS resistance in a methionine-independent manner. Collectively, our results demonstrate that methionine-mediated antagonism of anti-folate drugs occurs through sustained production of folate precursors.

Published
2018
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145. Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification.

Author

Bockman MR, Engelhart CA, Dawadi S, Larson P, Tiwari D, Ferguson DM, Schnappinger D, and Aldrich CC

Subjects
Antitubercular Agents chemistry, Microbial Sensitivity Tests, Molecular Structure, Nucleosides chemistry, Structure-Activity Relationship, Substrate Specificity, Antitubercular Agents pharmacology, Carbon-Nitrogen Ligases metabolism, Drug Resistance, Bacterial, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis enzymology, Nucleosides metabolism
Abstract

5'-[ N-(d-biotinoyl)sulfamoyl]amino-5'-deoxyadenosine (Bio-AMS, 1) possesses selective activity against Mycobacterium tuberculosis ( Mtb) and arrests fatty acid and lipid biosynthesis through inhibition of the Mycobacterium tuberculosis biotin protein ligase ( MtBPL). Mtb develops spontaneous resistance to 1 with a frequency of at least 1 × 10 -7 by overexpression of Rv3406, a type II sulfatase that enzymatically inactivates 1. In an effort to circumvent this resistance mechanism, we describe herein strategic modification of the nucleoside at the 5'-position to prevent enzymatic inactivation. The new analogues retained subnanomolar potency to MtBPL ( K D = 0.66-0.97 nM), and 5' R- C-methyl derivative 6 exhibited identical antimycobacterial activity toward: Mtb H37Rv, MtBPL overexpression, and an isogenic Rv3406 overexpression strain (minimum inhibitory concentration, MIC = 1.56 μM). Moreover, 6 was not metabolized by recombinant Rv3406 and resistant mutants to 6 could not be isolated (frequency of resistance <1.4 × 10 -10 ) demonstrating it successfully overcame Rv3406-mediated resistance.

Published
2018
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146. Structural and functional delineation of aerobactin biosynthesis in hypervirulent Klebsiella pneumoniae .

Author

Bailey DC, Alexander E, Rice MR, Drake EJ, Mydy LS, Aldrich CC, and Gulick AM

Subjects
Catalytic Domain, Cloning, Molecular, Crystallography, X-Ray, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression, Genetic Vectors chemistry, Genetic Vectors metabolism, Humans, Hydroxamic Acids metabolism, Kinetics, Klebsiella Infections microbiology, Klebsiella Infections pathology, Klebsiella pneumoniae genetics, Klebsiella pneumoniae isolation & purification, Klebsiella pneumoniae pathogenicity, Models, Molecular, Oxo-Acid-Lyases genetics, Oxo-Acid-Lyases metabolism, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Structure, Quaternary, Protein Structure, Tertiary, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Siderophores biosynthesis, Siderophores genetics, Substrate Specificity, Thermodynamics, Virulence Factors biosynthesis, Virulence Factors genetics, Hydroxamic Acids chemistry, Klebsiella pneumoniae enzymology, Oxo-Acid-Lyases chemistry, Siderophores chemistry, Virulence Factors chemistry
Abstract

Aerobactin, a citryl-hydroxamate siderophore, is produced by a number of pathogenic Gram-negative bacteria to aid in iron assimilation. Interest in this well-known siderophore was reignited by recent investigations suggesting that it plays a key role in mediating the enhanced virulence of a hypervirulent pathotype of Klebsiella pneumoniae (hvKP). In contrast to classical opportunistic strains of K. pneumoniae , hvKP causes serious life-threatening infections in previously healthy individuals in the community. Multiple contemporary reports have confirmed fears that the convergence of multidrug-resistant and hvKP pathotypes has led to the evolution of a highly transmissible, drug-resistant, and virulent "super bug." Despite hvKP harboring four distinct siderophore operons, knocking out production of only aerobactin led to a significant attenuation of virulence. Herein, we continue our structural and functional studies on the biosynthesis of this crucial virulence factor. In vivo heterologous production and in vitro reconstitution of aerobactin biosynthesis from hvKP was carried out, demonstrating the specificity, stereoselectivity, and kinetic throughput of the complete pathway. Additionally, we present a steady-state kinetic analysis and the X-ray crystal structure of the second aerobactin synthetase IucC, as well as describe a surface entropy reduction strategy that was employed for structure determination. Finally, we show solution X-ray scattering data that support a unique dimeric quaternary structure for IucC. These new insights into aerobactin assembly will help inform potential antivirulence strategies and advance our understanding of siderophore biosynthesis., (© 2018 Bailey et al.)

Published
2018
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147. Targeting protein biotinylation enhances tuberculosis chemotherapy.

Author

Tiwari D, Park SW, Essawy MM, Dawadi S, Mason A, Nandakumar M, Zimmerman M, Mina M, Ho HP, Engelhart CA, Ioerger T, Sacchettini JC, Rhee K, Ehrt S, Aldrich CC, Dartois V, and Schnappinger D

Subjects
Animals, Biotinylation drug effects, Female, Mice, Mice, Inbred C57BL, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis metabolism, Sulfurtransferases metabolism, Tuberculosis drug therapy, Antitubercular Agents pharmacology, Bacterial Proteins metabolism, Tuberculosis metabolism
Abstract

Successful drug treatment for tuberculosis (TB) depends on the unique contributions of its component drugs. Drug resistance poses a threat to the efficacy of individual drugs and the regimens to which they contribute. Biologically and chemically validated targets capable of replacing individual components of current TB chemotherapy are a major unmet need in TB drug development. We demonstrate that chemical inhibition of the bacterial biotin protein ligase (BPL) with the inhibitor Bio-AMS (5'-[ N -(d-biotinoyl)sulfamoyl]amino-5'-deoxyadenosine) killed Mycobacterium tuberculosis ( Mtb ), the bacterial pathogen causing TB. We also show that genetic silencing of BPL eliminated the pathogen efficiently from mice during acute and chronic infection with Mtb Partial chemical inactivation of BPL increased the potency of two first-line drugs, rifampicin and ethambutol, and genetic interference with protein biotinylation accelerated clearance of Mtb from mouse lungs and spleens by rifampicin. These studies validate BPL as a potential drug target that could serve as an alternate frontline target in the development of new drugs against Mtb ., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Published
2018
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149. Conformationally Constrained Cinnolinone Nucleoside Analogues as Siderophore Biosynthesis Inhibitors for Tuberculosis.

Author

Dawadi S, Boshoff HIM, Park SW, Schnappinger D, and Aldrich CC

Abstract

5'- O -[ N -(Salicyl)sulfamoyl]adenosine (Sal-AMS, 1 ) is a nucleoside antibiotic that inhibits incorporation of salicylate into siderophores required for bacterial iron acquisition and has potent activity against Mycobacterium tuberculosis ( Mtb ). Cinnolone analogues exemplified by 5 were designed to replace the acidic acyl-sulfamate functional group of 1 (p K a = 3) by a more stable sulfonamide linkage (p K a = 6.0) in an attempt to address potential metabolic liabilities and improve membrane permeability. We showed 5 potently inhibited the mycobacterial salicylate ligase MbtA (apparent K i = 12 nM), blocked production of the salicylate-capped siderophores in whole-cell Mtb , and exhibited excellent antimycobacterial activity under iron-deficient conditions (minimum inhibitor concentration, MIC = 2.3 μM). To provide additional confirmation of the mechanism of action, we demonstrated the whole-cell activity of 5 could be fully antagonized by the addition of exogenous salicylate to the growth medium. Although the total polar surface area (tPSA) of 5 still exceeds the nominal threshold value (140 Å) typically required for oral bioavailability, we were pleasantly surprised to observe introduction of the less acidic and conformationally constrained cinnolone moiety conferred improved drug disposition properties as evidenced by the 7-fold increase in volume of distribution in Sprague-Dawley rats., Competing Interests: The authors declare no competing financial interest.

Published
2018
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150. Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole.

Author

Minato Y, Dawadi S, Kordus SL, Sivanandam A, Aldrich CC, and Baughn AD

Subjects
Drug Synergism, Escherichia coli, Feedback, Physiological, Microbial Sensitivity Tests, Pterins metabolism, Tetrahydrofolates biosynthesis, Trimethoprim, Sulfamethoxazole Drug Combination pharmacology
Abstract

Trimethoprim (TMP)-sulfamethoxazole (SMX) is a widely used synergistic antimicrobial combination to treat a variety of bacterial and certain fungal infections. These drugs act by targeting sequential steps in the biosynthetic pathway for tetrahydrofolate (THF), where SMX inhibits production of the THF precursor dihydropteroate, and TMP inhibits conversion of dihydrofolate (DHF) to THF. Consequently, SMX potentiates TMP by limiting de novo DHF production and this mono-potentiation mechanism is the current explanation for their synergistic action. Here, we demonstrate that this model is insufficient to explain the potent synergy of TMP-SMX. Using genetic and biochemical approaches, we characterize a metabolic feedback loop in which THF is critical for production of the folate precursor dihydropterin pyrophosphate (DHPPP). We reveal that TMP potentiates SMX activity through inhibition of DHPPP synthesis. Our study demonstrates that the TMP-SMX synergy is driven by mutual potentiation of the action of each drug on the other.

Published
2018
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