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Abstract
Efflux pumps are one of the predominant microbial resistant mechanisms leading to the development of multidrug resistance. In Staphylococcus aureus, overexpression of NorA protein enables the efflux of antibiotics belonging to the class of fluoroquinolones and, thus, makes S. aureus resistant. Hence, NorA efflux pumps are being extensively exploited as the potential drug target to evade bacterial resistance and resensitize bacteria to the existing antibiotics. Although several molecules are reported to inhibit NorA efflux pump effectively, boronic acid derivatives were shown to have promising NorA efflux pump inhibition. In this regard, the current study exploits 6-(3-phenylpropoxy)pyridine-3-boronic acid to further improve the activity and reduce cytotoxicity using the bioisostere approach, a classical medicinal chemistry concept. Using the SWISS-Bioisostere online tool, from the parent compound, 42 compounds were obtained upon the replacement of the boronic acid. The 42 compounds were docked with modeled NorA protein, and key molecular interactions of the prominent compounds were assessed. The top hit compounds were further analyzed for their drug-like properties using ADMET studies. The identified potent lead, 5-nitro-2-(3-phenylpropoxy)pyridine (5-NPPP), was synthesized, and in vitro efficacy studies have been proven to show enhanced efflux inhibition, thus acting as a potent antibiotic breaker to resensitize S. aureus without elucidating any cytotoxic effect to the host Hep-G2 cell lines.
Highlights
Antibiotics are the first class of drugs that have been effective in treating many infections of clinical importance (Fernandes, 2006)
As a part of therapeutic potential, the antibacterial effect of boronic acid was known to suppress the production of virulence determinants and antibiotic-degrading enzymes to enhance the activity of antibiotics (Trippier and McGuigan, 2010)
Vabomere®, a drug composed of boronic acid and the b-lactam meropenem, has been marketed to treat urinary tract infections caused by (MDR) Pseudomonas and carbapenem-resistant Enterobacteriaceae (Griffith et al, 2019)
Summary
Antibiotics are the first class of drugs that have been effective in treating many infections of clinical importance (Fernandes, 2006). Several non-antibiotics such as reserpine, verapamil, flavones, isoflavones, porphyrin pheophorbide A, and acylated glycosides are reported to be NorA inhibitors that act as selective small-molecule modulators rather than clinical drug candidates (Schillaci et al, 2017) In this context, the efforts are focused on the design and synthesis of novel chemotypes, which could synergize with ciprofloxacin (CIP) against norA overexpressing S. aureus strains and impact on clinical relevance (Sabatini et al, 2011; Sabatini et al, 2013; Astolfi et al, 2017; Felicetti et al, 2017). Bioisosterism allows molecularly modifying the lead compound without compromising the drug target interaction, enhances the biological activity with improved pharmacokinetics, and reduces toxicity (Patani and LaVoie, 1996) In this regard, the current work aims to design new molecules from the reported lead compound by replacing the boronic acid moiety with a small molecule chemotype capable of restoring CIP activity on S. aureus strains by inhibition of NorA using SwissBioisostere (Wirth et al, 2013). This study combines systematically the interdisciplinary aspect of bioinformatics, medicinal chemistry, and microbiological studies to design and validate a promising NorA EPI
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