Abstract
Abstract
Multidrug-resistant bacterial infections present a serious challenge to global health. In addition to the spread of antibiotic resistance, some bacteria can form persister cells which are tolerant to most antibiotics and can lead to treatment failure or relapse. In the present work, we report the discovery of a new class of small molecules with potent antimicrobial activity against Gram-positive bacteria and moderate activity against Gram negative drug resistant bacterial pathogens. The lead compound SIMR 2404 had a minimal inhibitory concentration (MIC) of 2 µg/ml against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate Staphylococcus aureus (VISA). The MIC values against Gram negative bacteria such as Escherichia coli and Actinobacteria baumannii were between 8–32 µg/ml. Time kill experiments show that compound SIMR 2404 can rapidly kill tested bacteria. Compound SIMR 2404 was also found to rapidly kill MRSA persisters which display high levels of tolerance to conventional antibiotics. In antibiotic evolution experiments, MRSA quickly developed resistance to ciprofloxacin but failed to develop resistance to compound SIMR 2404 even after 24 serial passages. The rapid antibacterial activity against both active and persister MRSA and to a lesser extent against Gram negative bacteria, suggest the potential of these molecules for further evaluation as antibacterial agents.
Publisher
Research Square Platform LLC
Reference45 articles.
1. Antimicrobial resistance: a global multifaceted phenomenon;Prestinaci F;Pathogens and global health,2015
2. Superbugs but no drugs: steps in averting a post-antibiotic era;Hamad M;Drug discovery today,2019
3. J. e. a. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis;Murray CL;Lancet (London, England),2022
4. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis;Tacconelli E;The Lancet. Infectious diseases,2018
5. WHO. WHO publishes list of bacteria for which new antibiotics are urgently needed. (2017). Available online at: https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed (accessed November 20, 2022).