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This study explored the enantiocomplementary bioreduction of substituted 1-(arylsulfanyl)propan-2-ones in batch mode using four wild-type yeast strains and two different recombinant alcohol dehydrogenases from Lactobacillus kefir and Rhodococcus aetherivorans. The selected yeast strains and recombinant alcohol dehydrogenases as whole-cell biocatalysts resulted in the corresponding 1-(arylsulfanyl)propan-2-ols with moderate to excellent conversions (60–99%) and high selectivities (ee > 95%). The best bioreductions—in terms of conversion (>90%) and enantiomeric excess (>99% ee)—at preparative scale resulted in the expected chiral alcohols with similar conversion and selectivity to the screening reactions.

In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC 50 values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 μg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 μg/mL and against the E. faecalis strain with a MIC of 0.125 μg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nace Zidar reports financial support was provided by Slovenian Research Agency. Cristina D. Cruz, Paivi Tammela reports financial support was provided by Research Council of Finland. Marton Simon Czikkely reports financial support was provided by Hungarian Ministry of Culture and Innovation. Nace Zidar has patent New N-phenylpyrrolamide inhibitors of DNA gyrase and topoisomerase IV with antibacterial activity pending to University of Ljubljana. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Phage therapy is gaining increasing interest in the fight against critically antibiotic-resistant nosocomial pathogens. However, the narrow host range of bacteriophages hampers the development of broadly effective phage therapeutics and demands precision approaches. Here, we combine large-scale phylogeographic analysis with high-throughput phage typing to guide the development of precision phage cocktails targeting carbapenem-resistant Acinetobacter baumannii, a top-priority pathogen. Our analysis reveals that a few strain types dominate infections in each world region, with their geographical distribution remaining stable within 6 years. As we demonstrate in Eastern Europe, this spatiotemporal distribution enables preemptive preparation of region-specific phage collections that target most local infections. Finally, we showcase the efficacy of phage cocktails against prevalent strain types using in vitro and animal infection models. Ultimately, genomic surveillance identifies patients benefiting from the same phages across geographical scales, thus providing a scalable framework for precision phage therapy., Competing Interests: Declaration of interests M.K., T.S., H.H.M., O.M., G.A., B.E., B.P., and B.K. are inventors on a filed patent application of region-specific phage compositions (European Patent Office). B.K., T.S., M.K., B.E., and B.M.V. are employees of BRC-Bio Ltd. Hungary., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The negative membrane potential within bacterial cells is crucial in various essential cellular processes. Sustaining a hyperpolarised membrane could offer a novel strategy to combat antimicrobial resistance. However, it remains uncertain which molecules are responsible for inducing hyperpolarization and what the underlying molecular mechanisms are. Here, we demonstrate that chemically diverse antimicrobial peptides (AMPs) trigger hyperpolarization of the bacterial cytosolic membrane when applied at subinhibitory concentrations. Specifically, these AMPs adopt a membrane-induced amphipathic structure and, thereby, generate hyperpolarization in Escherichia coli without damaging the cell membrane. These AMPs act as selective ionophores for K + (over Na + ) or Cl - (over H 2 PO 4 - and NO 3 - ) ions, generating diffusion potential across the membrane. At lower dosages of AMPs, a quasi-steady-state membrane polarisation value is achieved. Our findings highlight the potential of AMPs as a valuable tool for chemically hyperpolarising bacteria, with implications for antimicrobial research and bacterial electrophysiology., (© 2024. The Author(s).)

This study presents the discovery of a new series of N -phenylpyrrolamide inhibitors of bacterial DNA gyrase with improved antibacterial activity. The most potent inhibitors had low nanomolar IC 50 values against Escherichia coli DNA gyrase (IC 50 ; 2-20 nM) and E. coli topoisomerase IV (22i, IC 50 = 143 nM). Importantly, none of the compounds showed activity against human DNA topoisomerase IIα, indicating selectivity for bacterial targets. Among the tested compounds, 22e emerged as the most effective against Gram-positive bacteria with minimum inhibitory concentration (MIC) values of 0.25 μg mL -1 against Staphylococcus aureus ATCC 29213 and MRSA, and 0.125 μg mL -1 against Enterococcus faecalis ATCC 29212. For Gram-negative bacteria, compounds 23b and 23c showed the greatest efficacy with MIC values ranging from 4 to 32 μg mL -1 against E. coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Acinetobacter baumannii ATCC 17978 and A. baumannii ATCC 19606. Notably, compound 23b showed promising activity against the clinically relevant Gram-negative pathogen Klebsiella pneumoniae ATCC 10031, with an MIC of 0.0625 μg mL -1 . Furthermore, compounds 23a and 23c exhibited significantly lower susceptibility to resistance development compared to novobiocin in S. aureus ATCC 29213 and K. pneumoniae ATCC 10031. Overall, the most promising compounds of this series showed excellent on-target potency, marking a significant improvement over previous N -phenylpyrrolamide inhibitors., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)