Breaking down resistance: Verapamil analogues augment the efficacy of antibiotics against Streptococcus pneumoniae via MATE transporter interference

Abstract

Pneumonia, an infectious lung disease, is a significant global health concern, claiming the lives of 740,180 children in 2019, which accounts for 14 % of pediatric deaths. Recently, the management of pediatric pneumonia has become complex due to exposure to indoor and outdoor environmental toxins. Notably, exposure to pollutants and antibiotic-resistant bacteria during community and hospital-acquired pneumonia poses a serious threat to patient outcomes. The development of antibiotic resistance against Streptococcus pneumoniae is driven by the DinF efflux pump protein, which expels antibiotics from bacterial cells, leading to multidrug resistance. Therefore, blocking DinF could serve as a strategy to combat antibiotic resistance. This study aimed to identify DinF inhibitors from compounds analogous to verapamil, a well-known DinF inhibitor, through computational techniques including molecular docking, molecular dynamics simulations, ADMET analysis, MMGBSA, quantum mechanics, and Network Pharmacology. After considering docking scores, results of MMGBSA, quantum mechanics, Molecular Dynamics Simulations, ADMET analysis and network pharmacology profiling four compounds namely netarsudil, rimegepant, GSK-1521498 and tariquidar were found as the most promising DinF inhibitors. Therefore, these compounds hold a great promise as leads to the development of potent DinF inhibitors; however, further studies are needed to warrant their clinical uses against antibiotic resistant Streptococcus pneumoniae-induced pneumonia.

Keywords

• Streptococcus pneumoniae
• MATE efflux pump DinF
• Antibiotic resistance
• Molecular docking
• MMGBSA
• Quantum mechanics