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Fosfomycin is a safe broad-spectrum antibiotic that has not achieved widespread use because of the emergence of fosfomycin-modifying enzymes. Inhibition of fosfomycin-modifying enzymes could be used to help combat pathogens like Mycobacterium abscessus. Our previous work identified several inhibitors for the enzyme FosB from Staphylococcus aureus. We have tested those same compounds for inhibition of FosM, the fosfomycin-modifying enzyme from M. abscessus. The work described here will be used as the basis for more detailed studies into the inhibition of FosM., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A clinically significant mechanism of tuberculosis resistance to the aminoglycoside kanamycin (KAN) is its acetylation catalyzed by upregulated Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. In search for inhibitors of Eis, we discovered an inhibitor with a substituted benzyloxy-benzylamine scaffold. A structure-activity relationship study of 38 compounds in this structural family yielded highly potent (IC 50 ∼ 1 μM) Eis inhibitors, which did not inhibit other acetyltransferases. Crystal structures of Eis in complexes with three of the inhibitors showed that the inhibitors were bound in the aminoglycoside binding site of Eis, consistent with the competitive mode of inhibition, as established by kinetics measurements. When tested in Mtb cultures, two inhibitors (47 and 55) completely abolished resistance to KAN of the highly KAN-resistant strain Mtb mc 2 6230 K204, likely due to Eis inhibition as a major mechanism. Thirteen of the compounds were toxic even in the absence of KAN to Mtb and other mycobacteria, but not to non-mycobacteria or to mammalian cells. This, yet unidentified mechanism of toxicity, distinct from Eis inhibition, will merit future studies along with further development of these molecules as anti-mycobacterial agents., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sylvie Garneau-Tsodikova reports financial support was provided by National Institutes of Health., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Many essential enzymes in bacteria remain promising potential targets of antibacterial agents. In this study, we discovered that dequalinium, a topical antibacterial agent, is an inhibitor of Staphylococcus aureus primase DnaG (SaDnaG) with low-micromolar minimum inhibitory concentrations against several S. aureus strains, including methicillin-resistant bacteria. Mechanistic studies of dequalinium and a series of nine of its synthesized analogues revealed that these compounds are single-stranded DNA bisintercalators that penetrate a bacterium by compromising its membrane. The best compound of this series likely interacts with DnaG directly, inhibits both staphylococcal cell growth and biofilm formation, and displays no significant hemolytic activity or toxicity to mammalian cells. This compound is an excellent lead for further development of a novel anti-staphylococcal therapeutic., (© 2021 Wiley-VCH GmbH.)

The rise and emergence of resistance to antifungal drugs by diverse pathogenic fungal strains have resulted in an increase in demand for new antifungal agents. Various heterocyclic scaffolds with different mechanisms of action against fungi have been investigated in the past. Herein, we report the synthesis and antifungal activities of 18 alkylated mono-, bis-, and trisbenzimidazole derivatives, their toxicities against mammalian cells, as well as their ability to induce reactive oxygen species (ROS) in yeast cells. Many of our bisbenzimidazole compounds exhibited moderate to excellent antifungal activities against all tested fungal strains, with MIC values ranging from 15.6 to 0.975μg/mL. The fungal activity profiles of our bisbenzimidazoles were found to be dependent on alkyl chain length. Our most potent compounds were found to display equal or superior antifungal activity when compared to the currently used agents amphotericin B, fluconazole, itraconazole, posaconazole, and voriconazole against many of the strains tested., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Since the discovery of the first aminoglycoside (AG), streptomycin, in 1943, these broad-spectrum antibiotics have been extensively used for the treatment of Gram-negative and Gram-positive bacterial infections. The inherent toxicity (ototoxicity and nephrotoxicity) associated with their long-term use as well as the emergence of resistant bacterial strains have limited their usage. Structural modifications of AGs by AG-modifying enzymes, reduced target affinity caused by ribosomal modification, and decrease in their cellular concentration by efflux pumps have resulted in resistance towards AGs. However, the last decade has seen a renewed interest among the scientific community for AGs as exemplified by the recent influx of scientific articles and patents on their therapeutic use. In this review, we use a non-conventional approach to put forth this renaissance on AG development/application by summarizing all patents filed on AGs from 2011-2015 and highlighting some related publications on the most recent work done on AGs to overcome resistance and improving their therapeutic use while reducing ototoxicity and nephrotoxicity. We also present work towards developing amphiphilic AGs for use as fungicides as well as that towards repurposing existing AGs for potential newer applications.