Mahdally Norhan H, George Riham F, Kashef Mona T, Al-Ghobashy Medhat, Murad Fathia E, Attia Ahmed S
Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Front Microbiol. 2021 Jul 5;12:700494. doi: 10.3389/fmicb.2021.700494. eCollection 2021.
The emergence of microbial resistance to the available antibiotics is a major public health concern, especially with the limited rate of developing new antibiotics. The utilization of anti-virulence agents is a non-conventional approach that can be used to combat microbial infection. In , many virulence factors are regulated by the Agr-mediated quorum sensing (QS). We developed a chemical compound that acts a potential Agr-inhibitor without reducing bacterial viability. The compound was designated staquorsin for S QS inhibitor. analyses confirmed the binding of staquorsin to the AgrA active site with an absolute binding score comparable to savirin, a previously described AgrA inhibitor. However, staquorsin turned out to be superior over savarin in not affecting the viability in concentrations up to 600 μM. On the other hand, savirin inhibited growth in concentrations as low as 25 μM. Moreover, staquorsin proved to be a potent inhibitor of the Agr system by inhibiting hemolysins, lipase production, and affecting biofilms formation and detachment. On the molecular level it significantly inhibited the effector transcript RNA III. testing, using the murine skin abscess model, confirmed the ability of staquorsin to modulate virulence by effectively controlling the infection. Twenty passages of in the presence of 40 μM staquorsin have not resulted in loss of activity as evidenced by maintaining its ability to reduce hemolysin production and RNA III transcript levels. In conclusion, we hereby describe a novel anti-virulence compound inhibiting the Agr-system and its associated virulence factors. It is active both and , and its frequent use does not lead to the development of resistance. These findings model staquorsin as a promising drug candidate to join the fierce battle against the formidable pathogen .
微生物对现有抗生素产生耐药性已成为一个重大的公共卫生问题，尤其是在新抗生素研发速度有限的情况下。使用抗毒力剂是一种可用于对抗微生物感染的非常规方法。在金黄色葡萄球菌中，许多毒力因子受Agr介导的群体感应（QS）调控。我们开发了一种化合物，它作为一种潜在的Agr抑制剂，且不会降低细菌活力。该化合物被命名为staquorsin作为金黄色葡萄球菌QS抑制剂。分析证实staquorsin与AgrA活性位点结合，其绝对结合分数与之前描述的AgrA抑制剂savirin相当。然而，事实证明staquorsin优于savarin，在浓度高达600μM时不影响金黄色葡萄球菌的活力。另一方面，savirin在低至25μM的浓度下就会抑制金黄色葡萄球菌的生长。此外，staquorsin通过抑制溶血素、脂肪酶的产生以及影响生物膜的形成和脱离，被证明是Agr系统的有效抑制剂。在分子水平上，它显著抑制效应转录本RNA III。使用小鼠皮肤脓肿模型进行的测试证实了staquorsin通过有效控制感染来调节金黄色葡萄球菌毒力的能力。在40μM staquorsin存在的情况下对金黄色葡萄球菌进行20代传代，并未导致活性丧失，这通过其维持降低溶血素产生和RNA III转录水平的能力得到证明。总之，我们在此描述了一种新型抗毒力化合物，它抑制金黄色葡萄球菌的Agr系统及其相关毒力因子。它在体内和体外均有活性，且频繁使用不会导致耐药性的产生。这些发现表明staquorsin是一种有前途的候选药物，可加入对抗这种强大病原体的激烈战斗。
