Quorum Sensing Laboratory, Centre of Research in Infectious Diseases, School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, India.
Department of Bioinformatics, School of Chemical & Biotechnology, SASTRA Deemed to be University, Thanjavur, India.
Front Cell Infect Microbiol. 2021 Aug 16;11:700198. doi: 10.3389/fcimb.2021.700198. eCollection 2021.
Efflux pumps are one of the predominant microbial resistant mechanisms leading to the development of multidrug resistance. In , overexpression of NorA protein enables the efflux of antibiotics belonging to the class of fluoroquinolones and, thus, makes 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 efficacy studies have been proven to show enhanced efflux inhibition, thus acting as a potent antibiotic breaker to resensitize without elucidating any cytotoxic effect to the host Hep-G2 cell lines.
外排泵是导致多药耐药性发展的主要微生物耐药机制之一。在 中，NorA 蛋白的过度表达使抗生素（属于氟喹诺酮类）外排，从而使 产生耐药性。因此，NorA 外排泵被广泛用作潜在的药物靶点，以规避细菌耐药性并使细菌重新对现有抗生素敏感。尽管有报道称几种分子能有效抑制 NorA 外排泵，但硼酸衍生物显示出有希望的 NorA 外排泵抑制作用。在这方面，本研究利用生物等排体方法（一种经典的药物化学概念）进一步改进活性并降低细胞毒性，利用 6-(3-苯氧基)吡啶-3-硼酸。使用 SWISS-Bioisostere 在线工具，从母体化合物中，在硼酸被取代后得到 42 种化合物。将这 42 种化合物与建模的 NorA 蛋白对接，并评估主要化合物的关键分子相互作用。对排名靠前的化合物进行进一步分析，以评估其药物样特性。通过 ADMET 研究确定了有潜力的先导化合物 5-硝基-2-(3-苯氧基)吡啶（5-NPPP），并已证明其具有增强的外排抑制作用，从而作为一种有效的抗生素破解剂，使 重新敏感，而不会对宿主 Hep-G2 细胞系产生任何细胞毒性作用。
