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Objectives Contezolid acefosamil is a novel O -acyl phosphoramidate prodrug of contezolid. In the current study, we aimed to systemically evaluate the efficacy of contezolid acefosamil against infections caused by multiple Gram-positive pathogens, and compare the efficacy of the prodrug by oral and intravenous administrations. Methods The in vivo pharmacodynamic efficacy of contezolid acefosamil was evaluated in mouse models of systemic (with five S. aureus , three S. pneumoniae and two S. pyogenes bacterial isolates) and thigh (with two S. aureus isolates) infections using linezolid as the reference agent. Results In both models, contezolid acefosamil administrated either orally or intravenously, demonstrated high antibacterial efficacy similar to linezolid, and the antibacterial efficacy of oral and intravenous contezolid acefosamil were comparable. Conclusions The high aqueous solubility and great efficacy of contezolid acefosamil support its clinical development as an injectable and oral antibiotic suitable for serious Gram-positive infections. [ABSTRACT FROM AUTHOR]

One new virginiamycin derivative, 'beilunmycin' (1), and three known virginiamycin antibiotics, 16-hydroxy-virginiamycin M1 (2), virginiamycin M2 (3), and virginiamycin M1 (4), were isolated from the culture of a mangrove-derived endophytic Streptomyces sp. 2BBP-J2. The structures were characterized on the basis of their spectroscopic data, and the absolute configuration of 1 was established by ECD calculations. Compounds 1–4 exhibited antibacterial activities against Gram-positive bacteria, with MIC values in the range of 0.5–16 μg/ml. All the compounds demonstrated strong protein translation-stalling activity, with minimal concentrations detected with pDualrep2 in the range of 1.9–5.9 nmol. [ABSTRACT FROM AUTHOR]

(E)-N,N-dimethyl-4-oxo-4-(4-(pyridin-4-yl)phenyl)but-2-enamide hydrochloride (IMB-YH-4py5-2H) is a novel Protein Kinase B (PknB) inhibitor with potent activity against Mycobacterium tuberculosis strains. In the present study, a sensitive and specific liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine IMB-YH-4py5-2H in rat plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and separation was performed on an XTerra MS C18 column (2.1×50 mm, 3.5 μm) with gradient elution (methanol and 0.1% formic acid) at a flow rate of 0.3 mL/min. Detection was performed in multiple reaction monitoring (MRM) mode. Linear calibration curves were obtained over a concentration range of 1−100 ng/mL. The intra-day and inter-day precisions were lower than 8.46%, and the accuracies ranged from -8.71% to 12.36% at all quality control levels. The extraction recoveries were approximately 70%, and the matrix effects were negligible. All quality control samples were stable under different storage conditions. The validated method was successfully applied to a preclinical pharmacokinetic study in Sprague-Dawley rats. IMB-YH-4py5-2H demonstrated improved pharmacokinetic properties (higher exposure level) compared with its leading compound. IMB-YH-4py5-2H was also distributed throughout the lung pronouncedly, especially inside alveolar macrophages, indicating its effectiveness against lower respiratory infections. [ABSTRACT FROM AUTHOR]

Pharmacological efficacy is based on the drug concentration in target tissues, which usually cannot be represented by the plasma concentration. The purpose of this study was to compare the pharmacokinetic characteristics of gemifloxacin in plasma and skeletal muscle and evaluate its tissue penetration in both healthy and MRSA (methicillin-resistant Staphylococcus aureus)-infected rats. A microdialysis (MD) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine free gemifloxacin concentrations in rat plasma and skeletal muscle simultaneously. The in vivo recoveries of MD were 23.21% ± 3.42% for skeletal muscle and 20.62% ± 3.19% for plasma, and were concentration independent. We provided evidence that the method developed here meets FDA requirements. Additionally, this method was successfully applied to the determination of free gemifloxacin in rats. Muscle and blood dialysates were collected after an 18 mg/kg intravenous bolus dose. The mean areas under the concentration-time curves (AUCs) from 0 to 9 h for skeletal muscle and plasma were 3641.50 ± 915.65 h*ng/mL and 7068.32 ± 1964.19 h*ng/mL in MRSA-infected rats and 3774.72 ± 700.36 h*ng/mL and 6927.49 ± 1714.86 h*ng/mL in healthy rats, respectively. There was no significant difference (P>0.05) in gemifloxacin exposure between healthy rats and MRSA-infected rats for plasma or muscle. The low ratio of AUC0-9 muscle to AUC0-9 plasma suggested lower drug exposure in skeletal muscle than in plasma for both healthy and MRSA-infected rats. Our study suggested that the administration of gemifloxacin according to drug levels in plasma to treat local infection is unreasonable and might result in an inadequate dose regimen. [ABSTRACT FROM AUTHOR]

In this work, the thermal bistability of magnons in yttrium iron garnet microspheres was experimentally characterized. Using high quality factor optical whispering gallery modes in the microsphere, the temperature change caused by the microwave pump is precisely measured by probing the optical resonance wavelength shift. It is found that temperature change also induces the magnonic frequency shift and the frequency shift depends on the crystal axis direction of the material. With some appropriate alignment of the magnetic field and the microsphere, the magnonic frequency shift induced by the thermal bistability from the microwave can be suppressed. Our results show its potential use in future experiments on magnon-based transducers. [ABSTRACT FROM AUTHOR]

Some synthetic chemicals, which have been shown to disrupt thyroid hormone (TH) function, have been detected in surface waters and people have the potential to be exposed through water-drinking. Here, the presence of thyroid-active chemicals and their toxic potential in drinking water sources in Yangtze River Delta were investigated by use of instrumental analysis combined with cell-based reporter gene assay. A novel approach was developed to use Monte Carlo simulation, for evaluation of the potential risks of measured concentrations of TH agonists and antagonists and to determine the major contributors to observed thyroid receptor (TR) antagonist potency. None of the extracts exhibited TR agonist potency, while 12 of 14 water samples exhibited TR antagonistic potency. The most probable observed antagonist equivalents ranged from 1.4 to 5.6 µg di-n-butyl phthalate (DNBP)/L, which posed potential risk in water sources. Based on Monte Carlo simulation related mass balance analysis, DNBP accounted for 64.4% for the entire observed antagonist toxic unit in water sources, while diisobutyl phthalate (DIBP), di-n-octyl phthalate (DNOP) and di-2-ethylhexyl phthalate (DEHP) also contributed. The most probable observed equivalent and most probable relative potency (REP) derived from Monte Carlo simulation is useful for potency comparison and responsible chemicals screening. [ABSTRACT FROM AUTHOR]

ABSTRACT Several lines of evidence show that the nephrotoxic effect of melamine (MEL) in animals is consistent with combined ingestion of MEL and cyanuric acid (CYA). The aim of the present study was to compare the toxicokinetics of MEL in the presence and absence of CYA, and to elucidate the correlation between toxicity and kinetic properties of MEL. Sprague-Dawley rats were administered a single oral dose of MEL (100 mg kg−1) with or without CYA (100 mg kg−1). Plasma and tissue samples were analyzed by liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay. Significant changes in toxicokinetic parameters of MEL such as lower maximum concentration (7.4 ± 3.5 vs 78.0 ± 11.0 µg ml−1) and area under curve (94.9 ± 53.5 vs 295.1 ± 93.7 µg h ml−1), higher plasma elimination half-life (7.0 ± 3.3 vs 2.5 ± 0.3 h) and volume of distribution (11 505.5 ± 5030.3 vs 1312.7 ± 337.7 ml kg−1), as well as significantly higher concentration of MEL in rat kidney (2.96-274.15 vs < 1 µg g−1) were detected in the CYA co-administration group when compared with MEL alone group ( P < 0.05). The differences in kinetic parameters between the two groups meant that CYA co-administration could lower absorption, slow excretion and induce tissue accumulation of MEL, which correlated well with the generation and development of renal toxicity. In conclusion, co-administration with CYA leads to the alteration of the kinetic characteristics of MEL, which provides an additional explanation for renal toxicity. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Twenty-five new derivatives of 8-hydroxycycloberberine (1) were synthesized and evaluated for their activities against Gram-positive bacteria, taking 1 as the lead. Part of them displayed satisfactory antibacterial activities against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-intermediate Staphylococcus aureus (VISA). Especially, compound 15a displayed an excellent anti-MRSA activity with MICs (minimum inhibitory concentrations) of 0.25–0.5 μg/mL, better than that of 1. It also displayed high stability in liver microsomes and whole blood, and the LD50 value of over 65.6 mg·kg−1 in mice via intravenous route, suggesting a good druglike feature. The mode of action showed that 15a could effectively suppress topo IV-mediated decatenation activity at the concentration of 7.5 μg/mL, through binding a different active pocket of bacterial topo IV from quinolones. Taken together, the derivatives of 1 constituted a promising kind of anti-MRSA agents with a unique chemical scaffold and a specific biological mechanism, and compound 15a has been chosen for the next investigation. [ABSTRACT FROM AUTHOR]

Nineteen new quinoline derivatives were prepared via the Mannich reaction and evaluated for their antibacterial activities against both Gram-positive (G+) and Gram-negative (G−) bacteria, taking compound 1 as the lead. Among the target compounds, quinolone coupled hybrid 5d exerted the potential effect against most of the tested G+ and G− strains with MIC values of 0.125–8 μg/mL, much better than those of 1. Molecular-docking assay showed that compound 5d might target both bacterial LptA and Top IV proteins, thereby displaying a broad-spectrum antibacterial effect. This hybridization strategy was an efficient way to promote the antibacterial activity of this kind, and compound 5d was selected for the further investigation, with an advantage of a dual-target mechanism of action. [ABSTRACT FROM AUTHOR]

Highlights • Two new aac(6′)-aph(2″) transposon structures were found in Enterococcus faecalis from Beijing, China. • Truncated aac(6′)-aph(2″) transposons were not always related to high plasmid location rate and high transfer efficiency. • Truncated aph(2″)-Ia region was identified upstream of a type III transposon with different rates among transposon groups. • Truncated aph(2″)-Ia region had similar positive rate trend as transposon plasmid location and conjugation-positive rates. ABSTRACT Transfer of aac(6′)-aph(2″) transposons mediating high-level gentamicin resistance (HLGR) in Enterococcus faecalis is a serious problem in the clinic. However, factors affecting the transfer of aac(6′)-aph(2″) have not yet been elucidated. The current study aimed to examine the genetic and molecular basis of HLGR in E. faecalis strains isolated in Beijing (China) and to clarify the relationship between transfer efficiency of aac(6′)-aph(2″) transposons and the transposon structure/location. A total of five transposon structures were identified by PCR mapping of the corresponding transposon regions, including a Tn 5281 -like non-truncated transposon and four truncated transposons. A plasmid location study of aac(6′)-aph(2″) by Southern blot following S1-PFGE and filter mating conjugation experiments demonstrated that plasmid location rates correlated with conjugation-positive rates. Chromosome walking to identify the sequence upstream of a representative type III truncated transposon found a truncated aph(2″)-Ia region, and further PCR analysis of this region among strains from different groups revealed similar a positive rate trend as the transposon plasmid location rate and conjugation-positive rate. In conclusion, aac(6′)-aph(2″) transposons were of different structures in E. faecalis strains from Beijing, with two new transposon structures that have not been reported elsewhere. Presence of the truncated aph(2″)-Ia region upstream of some truncated transposons suggests recombination between aminoglycoside-modifying enzyme genes. Possible links exist among plasmid location, conjugation and the presence of truncated aph(2″)-Ia upstream of the transposon. [ABSTRACT FROM AUTHOR]

• 34 new monobactam derivatives are synthesized and evaluated for anti- Gram-negative bacteria. • Compounds 8p , 8r showed comparable activities with AZN, with MIC values of 0.125–32 μg/mL. • They exhibited good synergistic effect on enzyme-producing G− bacteria combined with Avibactam. • Compounds 8p, 8r displayed excellent safety profiles both in vitro and in vivo. Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative bacteria. Among them, compounds 8p and 8r displayed moderate potency with MIC values of 0.125–32 μg/mL against most tested Gram-negative strains, comparable to AZN. Meanwhile, the combination of 8p and 8r with avibactam as a β-lactamases inhibitor, in a ratio of 1:16, showed a promising synergistic effect against both ESBLs- and NDM-1-producing K. pneumoniae , with significantly reduced MIC values up to 8-fold and >256-fold respectively. Furthermore, both of them demonstrated excellent safety profiles both in vitro and in vivo. The results provided powerful information for further structural optimization of monobactam antibiotics to fight β-lactamase-producing resistant Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

Aim: To investigate the proliferation regulatory effect of cone-rod homeobox (CRX) in retinal pigment epithelium (RPE) and retinoblastoma (RB) cells to explore the potential application and side effect (oncogenic potential) of CRX-based gene therapy in RPE-based retinopathies., Methods: Adult human retinal pigment epithelial (ARPE)-19 and human retinal pigment epithelial (RPE)-1 cells and Y79 RB cell were used in the study. Genetic manipulation was performed by lentivirus-based technology. The cell proliferation was determined by a CellTiter-Glo Reagent. The mRNA and protein levels were determined by quantitative real-time polymerase chain reaction (qPCR) and Western blot assay. The transcriptional activity of the promoter was determined by luciferase reporter gene assay. The bindings between CRX and transcription factor 7 (TCF7) promoter as well as TCF7 and the promoters of TCF7 target genes were examined by chromatin immunoprecipitation (ChIP) assay. The transcription of the TCF7 was determined by a modified nuclear run-on assay., Results: CRX overexpression and knockdown significantly increased ( n =3, P <0.05 in all the cells) and decreased ( n =3, P <0.01 in all the cells) the proliferation of RPE and RB cells. CRX overexpression and knockdown significantly increased and deceased the mRNA levels of Wnt signaling target genes [including MYC proto-oncogene ( MYC ), JUN , FOS like 1 ( FOSL1 ), CCND1 , cyclin D2 ( CCND2 ), cyclin D3 ( CCND3 ), cellular communication network factor 4 ( CCN4 ), peroxisome proliferator activated receptor delta ( PPARD ), and matrix metallopeptidase 7 ( MMP7 )] and the luciferase activity driven by the Wnt signaling transcription factor (TCF7). TCF7 overexpression and knockdown significantly increased and decreased the proliferation of RPE and RB cells and depletion of TCF7 significantly abolished the stimulatory effect of CRX on the proliferation of RPE and RB cells. CRX overexpression and knockdown significantly increased and decreased the mRNA level of TCF7 and the promoter of TCF7 was significantly immunoprecipitated by CRX antibody., Conclusion: CRX transcriptionally activates TCF7 to promote the proliferation of RPE and RB cells in vitro . CRX is a potential target for RPE-based regenerative medicine. The potential risk of this strategy, tumorigenic potential, should be considered., Competing Interests: Conflicts of Interest: Zhao N, None; Li YY, None; Xu JM, None; Yang MY, None; Li YZ, None; Lam TC, None; Zhou L, None; Tong QH, None; Zhang JT, None; Wang SZ, None; Hu XX, None; Wu YF, None; Lu QK, None; Lang TY, None., (International Journal of Ophthalmology Press.)

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the mechanism of non-carbapenemase carbapenem resistance is still unclear. In the current study, we investigated the contributions of point mutations in mexR , oprD , and ftsI to carbapenem resistance in P. aeruginosa during in vivo evolution studies with consecutive clinical isolates. Real-time qPCR and Electrophoretic Mobility Shift Assay demonstrated that MexR (Gln55Pro) mutation increased MexAB efflux pump genes expression by altering MexR's binding capacity, leading to a four- to eight-fold increase in meropenem MIC in the Pae d1 Green ∆ mexR and PAO1∆ mexR mutants. The OprD (Trp415*) truncation affected porin structure, and the constructed mutant Pae d1 Green oprD Trp415* increased meropenem MIC by 16-fold (from 0.25 to 4 µg/mL). The contribution of ftsI mutation to meropenem resistance was confirmed by clinical linkage analysis and was estimated to cause a two-fold increase in meropenem MIC by comparing the resistant clinical isolate with the Pae d1 Green oprD Trp415*∆ mexR double mutant. The study found that the oprD Trp415* allele alone accounts for the imipenem MIC in clinical isolates, while the ∆ mexR and ftsI Arg504Cys alleles do not contribute to imipenem resistance. In conclusion, we identified and explored the contributions of mexR , oprD, and ftsI mutations to high level non-carbapenemase carbapenem resistance in P. aeruginosa . These findings highlight the interplay of different mutations in causing non-carbapenemase carbapenem-resistance in P. aeruginosa ., Importance: The emergence of carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a significant global health threat, complicating treatment options for infections caused by this pathogen. Understanding the mechanisms behind non-carbapenemase carbapenem resistance is critical for developing effective therapeutic strategies. This study provides crucial insights into how specific point mutations in key genes- mexR , oprD , and ftsI -contribute to carbapenem resistance, particularly the MexR (Gln55Pro) mutation's effect on efflux pump expression and the OprD (Trp415*) truncation's impact on porin structure. The findings elucidate the complex interplay of these mutations, highlighting their roles in conferring high-level resistance, and underscore the imperative for continued research to inform therapeutic strategies against CRPA infections.

Single atoms are interesting candidates for studying quantum optics and quantum information processing. Recently, trapping and manipulation of single atoms using tight optical dipole traps has generated considerable interest. Here we report an experimental investigation of the dynamics of atoms in a modified optical dipole trap with a backward propagating dipole trap beam, where a change in the two-atom collision rate by six times has been achieved. The theoretical model presented gives a prediction of high probabilities of few-atom loading rates under proper experimental conditions. This work provides an alternative approach to the control of the few-atom dynamics in a dipole trap and the study of the collective quantum optical effects of a few atoms.

Microresonators on a photonic chip could enhance nonlinear optics effects and thus are promising for realizing scalable high-efficiency frequency conversion devices. However, fulfilling phase matching conditions among multiple wavelengths remains a significant challenge. Here, we present a feasible scheme for degenerate sum-frequency conversion that only requires the two-mode phase matching condition. When the drive and the signal are both near resonance to the same telecom mode, an on-chip photon-number conversion efficiency up to 42% is achieved, showing a broad tuning bandwidth over 250 GHz. Furthermore, cascaded Pockels and Kerr nonlinear optical effects are observed, enabling the parametric amplification of the optical signal to distinct wavelengths in a single device. The scheme demonstrated in this Letter provides an alternative approach to realizing high-efficiency frequency conversion and is promising for future studies on communications, atom clocks, sensing, and imaging.

Twenty-three polymyxin analogs with variations at nine amino acid positions were synthesized and assessed for antimicrobial activity and renal cytotoxicity. Compounds M 2 , 14 , S 2 , and 16 (MIC = 0.125-4 μg/mL) had similar or stronger activities against susceptible and drug-resistant strains of Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , and Acinetobacter baumannii compared to polymyxin B (MIC = 1-2 μg/mL). Most synthesized compounds (50% cytotoxic concentration, CC 50 ≥ 200 μg/mL) exhibited lower cytotoxicity than polymyxin B (CC 50 = 99 ± 6 μg/mL). Polymyxin S 2 showed high plasma stability in vitro and strong efficacy in a mouse systemic infection model (ED 50 = 0.9 mg/kg) against NDM-1-producing Klebsiella pneumoniae , suggesting that it is a potential candidate for drug development. The activity and cytotoxicity results indicated that the amino acids at positions 2, 3, 6, and 7 might be replaced. Effects on activity and cytotoxicity linked to changes in the number of positively charged amino acids varied among different cyclopeptide skeletons, but the underlying mechanisms are unknown.

Introduction: The clinical and molecular characteristics of hypervirulent Klebsiella pneumoniae (hvKp) in various provinces of China have been reported, however, there have been few reports in Hebei Province, North China., Methodology: The hvKp was identified by PCR amplification of hypervirulence-related genes, the hypermucoviscous phenotype was determined by the "string test", the drug susceptibility analysis was performed using the VITEK® 2 Compact Bacterial Identification and Monitoring System. Logistic regression was used to identify risk factors for hvKp infection. The molecular epidemiological characteristics of the strains were analyzed by pulsed-field gel electrophoresis (PFGE), and the capsular serotype of hvKp strain was detected by PCR., Results: Overall, 52.21% (59/113) of K. pneumoniae isolates were hvKp, and the ratios of patients with older ages or a higher PMN cell count among hvKp infection were higher than those among classical Klebsiella pneumoniae (cKp) infection. hvKp are more susceptible to antibacterial drugs than cKp, and one ESBLs-producing hvKp strain was detected. The main capsular serotype of hvKp were K2, K57 and K1. PFGE indicated that the 59 strains of hvKp could be classified into 51 PFGE band types, forming 6 PFGE clusters., Conclusions: In this study, the detection rate of hvKp was 52.21% (59/113) identified by virulence genes. People with older ages or a higher PMN cell count are more likely to gain hvKp infection. ESBLs-producing hvKp is emerging, indicating the importance of epidemiologic surveillance and clinical awareness of this pathogen in this region., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2020 Yan Yang, Jian-Hua Liu, Xin-Xin Hu, Wei Zhang, Tong-Ying Nie , Xin-Yi Yang, Xiu-Kun Wang, Cong-Ran Li, Xue-Fu You.)

Nonlinear optical effects in integrated microcavities have been studied extensively with the advantages of strong light-matter interaction, great scalability, and stability due to the small mode volume. However, the pump lasers stimulating nonlinear effects impose obstacles for practical applications, since the material absorption causes thermal resonance drift and instability. Here we experimentally demonstrate an all-optical control of the thermal behavior in optical microcavities for tunable doubly-resonant second-harmonic (SH) generation on an integrated photonic chip. Through an auxiliary control laser, the temperature of a selected microring can be efficiently changed, thus allowing precise frequency tuning of the doubly-resonant wavelength while eliminating the distortion of the lineshape induced by the thermo-optic effect. Although the phase-matching conditions will limit the tuning range of 55GHz, the technique is still potential to achieve a larger tuning range in combination with temperature regulation. Additionally, this approach has the advantage of quick reconfiguration, showing a fast modulation rate up to about 256 kHz. The theoretical model behind our experimental scheme is universal and applicable to other microcavity-enhanced nonlinear optical processes, and our work paves the way for controlling and utilizing the thermal effect in the applications of microcavities.

Cavity-enhanced optical controlling is experimentally observed with a low-control laser power in a cavity-atom ensemble system. Here, the three-level atoms are coupled with two optical modes of a Fabry-Perot cavity, where a new theoretical model is developed to describe the effective three-wave mixing process between spin-wave and optical modes. By adjusting either temperature or cavity length, we demonstrate the precise frequency tuning of the hybrid optical-atomic resonances. When the doubly-resonant condition is satisfied, the probe laser can be easily modulated by a control laser. In addition, interesting non-Hermitian physics are predicted theoretically and demonstrated experimentally, and all-optical switching is also achieved. Such a doubly-resonant cavity-atom ensemble system without a specially designed cavity can be used for future applications, such as optical signal storage and microwave-to-optical frequency conversion.

To extend the coherence of quantum transitions for laser locking, as well as increase the compactness and stability of the experimental setup, we propose to utilize photonic integrated resonators with high second-harmonic (SH) generation efficiencies as reliable frequency doublers that link the desired frequencies with the frequency references. In this Letter, a sufficiently strong SH signal up to microwatts was generated by a photonic integrated frequency doubler using a milliwatt infrared (IR) laser source. Furthermore, an increased SH generation bandwidth covering Rb85 and Rb87D 2 transition lines, as well as saturated absorption spectroscopy, was demonstrated by tuning the pump power and chip temperature. Here we present, to the best of our knowledge, the first successful locking of an IR laser to Rb saturated absorption lines via a photonic chip frequency doubler.

A series of novel thioether or sulfoxide-type pleuromutilin derivatives containing heteroaromatic substituents at the end of C14 side chain were designed and synthesized. All of the derivatives were evaluated for their in vitro antibacterial activity. Some of them showed good to excellent antibacterial activity comparable to retapamulin and azamulin in most of the tested Gram-positive pathogens. In this work, a five-membered heterocyclic moiety, a pyrimidine-heterocyclic moiety, or a benzoheterocyclic moiety was introduced in the C14 side chain to increase the structural diversity of the pleuromutilin derivatives. The antibacterial results reveal that the thioether-containing pleuromutilin derivatives exert a more potency activity than the sulfoxide-type derivatives against Gram-positive pathogens. The structure-activity relationship summarized in this work may provide with some interesting clues as to which functionalities are beneficial for high antimicrobial activity of the pleuromutilin derivatives., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

In this paper, 26 natural polymyxin components and a new derivative S 2 were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. The toxicities were obviously different between the components. Only some of the components were tested for toxicity in vivo. Compounds E 2 , E 2 -Val, A 2 , M 2 , D 2 , and S 2 showed obviously lower renal cytotoxicity and acute toxicity than polymyxins B and E. The in vivo nephrotoxicity of E 2 , M 2 , and S 2 was similar to that of polymyxin E. Compound S 2 , with four positive charges, was especially interesting as it possessed both increased efficacy and decreased toxicity. The SAR and toxicity studies indicated that further structural modification could concentrate on polymyxin S. The results also indicated that S 2 could be a new drug candidate.

Two new amicoumacins, named Damxungmacin A ( 1 ) and B ( 2 ), were isolated from the culture broth of a soil-derived bacterium Bacillus subtilis XZ-7. Their chemical structures were elucidated by spectroscopic studies (UV, IR, NMR and HR-ESI-MS). Compound 1 possessed a 1,4-diazabicyclo[2.2.1]heptane-2-one ring system in its structure, which was reported for the first time, while 2 had a 1-acetylmorpholine-3-one moiety, which was naturally rare. Compound 1 exhibited moderate to weak cytotoxic activities against three human tumor cell lines (A549, HCT116 and HepG2) with IC 50 values of 13.33, 14.34 and 13.64 μM, respectively. Meanwhile, compound 1 showed weak antibacterial activities against some strains of Staphylococcus epidermidis , while compound 2 at 16 μg/mL did not show antibacterial activity.

MRX-I is a potent oxazolidinone antibiotic against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), penicillin-intermediate S. pneumoniae (PISP), and vancomycin-resistant enterococci (VRE). In this study, the in vivo efficacy of orally administered MRX-I was evaluated using linezolid as a comparator. MRX-I showed the same or better efficacy than linezolid in both systemic and local infection models against the tested strains.

Background: Chinfloxacin is a novel synthetic fluoroquinolone with a structure similar to moxifloxacin. The in vitro activity of chinfloxacin was evaluated in the current study., Method: Chinfloxacin was tested against a total of 1,739 clinical isolates representing 23 species using the agar dilution method. Studies of bactericidal activity, including minimum bactericidal concentrations (MBC) and time-kill curve determinations, were conducted according to the recommendations of the Clinical and Laboratory Standards Institute., Results: Minimum inhibitory concentrations (MIC)(50)s and MIC(90)s of chinfloxacin were found to be the same or 2-fold lower than those of moxifloxacin against gram-positive isolates except for Streptococcus pyogenes (against which chinfloxacin showed similar MIC(50) as moxifloxacin but 2-fold higher MIC(90)), and the same as or 2-fold higher than those of moxifloxacin against gram-negative isolates. Chinfloxacin showed potent bactericidal activity with MBC/MIC ratios in the range of 1-2 for almost all the isolates tested. Time-kill curves further demonstrated chinfloxacin as a concentration-dependent bactericidal agent usually effective at concentrations of 2 MIC or higher., Conclusion: Chinfloxacin showed similar in vitro activity as moxifloxacin., (Copyright © 2012 S. Karger AG, Basel.)