Abstract

The serious challenge posed by multidrug-resistant bacterial infections with concomitant treatment failure and high mortality rates presents an urgent threat to the global health. We herein report the discovery of a new class of potent antimicrobial compounds that are highly effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The compounds were efficiently synthesized in one-pot employing a cascade of Groebke–Blackburn–Bienaymé and aza-Michael addition reactions. Phenotypic screening of the pilot library against various bacterial species including methicillin-sensitive and MRSA strains, has identified potent chemotypes with minimal inhibitory concentrations (MIC) of 3.125–6.25 μg/ml. The most potent compounds were fast-acting at eradicating exponentially growing MRSA, with killing achieved after 30 min of exposure to the compounds. They were also able to kill MRSA persister cells which are tolerant to most available medications. Microscopic analysis using fluorescence microscope and atomic force microscope indicate that these compounds lead to disruption of bacterial cell envelopes. Most notably, bacterial resistance toward these compounds was not observed after 20 serial passages in stark contrast to the significant resistance developed rapidly upon exposure to a clinically relevant antibiotic. Furthermore, the compounds did not induce significant hemolysis to human red blood cells. In vivo safety studies revealed a high safety profile of these motifs. These small molecules hold a promise for further studies and development as new antibacterial agents against MRSA infections.

Highlights

  • The ongoing COVID-19 pandemic is a wake-up call to seriously reconsider our preparedness to tackle infections (Aghila Rani et al, 2021)

  • methicillin-resistant Staphylococcus aureus (MRSA)-3 persisters were completely eradicated in a time-killing experiment after only 1 h of exposure to the compounds 5 × MIC for 6l and 10 × MIC 6s and 6t (Figures 4D–F). These results indicate that the test compounds are highly active and can rapidly kill dormant and quiescent persister MRSA and offers further evidence that compounds damage cell membranes

  • We have identified new compounds that possess potent antibacterial activity against MDR S. aureus including MRSA persisters

Read more

Summary

Introduction

The ongoing COVID-19 pandemic is a wake-up call to seriously reconsider our preparedness to tackle infections (Aghila Rani et al, 2021). GRAPHICAL ABSTRACT | Antibacterial activity of small molecules which eradicate methicillin-resistant Staphylococcus aureus (MRSA) persisters. The World Health Organization (WHO) has declared a list of priority MDR pathogens causing high morbidity and mortality worldwide as priority targets for the discovery and development of novel antimicrobial drugs (WHO, 2017; Tacconelli et al, 2018). One of the priority MDR pathogens is methicillin-resistant Staphylococcus aureus (MRSA), a Gram-positive bacterial pathogen that causes community and healthcare-associated infections with higher rates of morbidity and mortality in comparison to methicillin-sensitive S. aureus (Gardete and Tomasz, 2014; Turner et al, 2019). In addition to its resistance to antibiotics, treatment of MRSA infections is further complicated by its ability to form drug tolerant biofilms and persister cells (Lewis, 2005). More recent evidence demonstrates that Staphylococcus aureus can form persisters intracellularly upon antibiotic exposure (Peyrusson et al, 2020)

Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call