Development of an Antibiotic Resistance Breaker to Resensitize Drug-Resistant Staphylococcus aureus: In Silico and In Vitro Approach

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.

Polymer based dual drug delivery system for targeted treatment of fluoroquinolone resistant Staphylococcus aureus mediated infections

“…However, the combinatorial treatment (5-NPPP and CIP) significantly reduced CFU/mL. This corroborates with the previously reported data that 5-NPPP in combination with CIP exhibits an increased activity with a 16-fold reduction in concentration CIP 25 , as shown in Fig. 14 .…”

“…It was identified and proved to be a promising efflux pump inhibitor and an inhibitor of biofilm formation, as observed through the results of in vitro studies. The synergistic efficacy of the compound was explored in combination with Ciprofloxacin for treating S. aureus -mediated Soft Skin Infections (SSIs) 25 . Nanotechnology advancements have helped researchers explore it as a medium for drug delivery applications.…”

Effect of palladium(II) complexes on NorA efflux pump inhibition and resensitization of fluoroquinolone-resistant Staphylococcus aureus: in vitro and in silico approach

“…The individual concentrations of both compounds were also plated to serve as controls and references for the synergistic effects observed. Following the approach described in the MIC experiment, the overnight culture of SA1199B was suitably diluted and inoculated in 96-well plates ( Thamilselvan et al., 2021 ). The plates were incubated for 24 h at 37°C, the optical density was measured at 595 nm and, subsequently, the percentage of inhibition was calculated.…”

“…The percentage cell viability was calculated with reference to the untreated control cells using the below-given formula: 2.12 Docking studies Docking simulations were conducted between the NorA EP (PDB ID: 7LO7) and QSL_Pd 5A using the Autodock 4.2 suite. The NorA protein structure model, acquired from a previous study conducted by our lab using the I-TASSER (Iterative Threading ASSEmbly Refinement) server (https://zhanglab.dcmb.med.umich.edu/I-TASSER/) (Thamilselvan et al, 2021), was employed. The protein preparation phase involved reading the NorA protein protein data bank (PDB) file, addressing missing atoms and adding polar hydrogen atoms.…”

Polymer-based dual drug delivery system for targeted treatment of fluoroquinolone-resistant Staphylococcus aureus mediated infections

“…It was identi ed and proved to be a promising e ux pump inhibitor and an inhibitor of bio lm formation, as observed through the results of in-vitro studies. The synergistic e cacy of the compound was explored in combination with Cipro oxacin for treating S. aureus-mediated Soft Skin Infections (SSIs) 25 . Advancement in the eld of nanotechnology has helped researchers to explore it as a medium for drug delivery applications.…”