School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublingrid.8217.c, Dublin, Ireland.
School of Pharmacy and Biomedical Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
Microbiol Spectr. 2022 Jun 29;10(3):e0117521. doi: 10.1128/spectrum.01175-21. Epub 2022 Jun 1.
Staphylococcus aureus infections have become a major challenge in health care due to increasing antibiotic resistance. We aimed to design small molecule inhibitors of S. aureus surface proteins to be developed as colonization inhibitors. We identified allantodapsone in an initial screen searching for inhibitors of clumping factors A and B (ClfA and ClfB). We used microbial adhesion assays to investigate the effect of allantodapsone on extracellular matrix protein interactions. Allantodapsone inhibited S. aureus Newman adhesion to fibrinogen with an IC of 21.3 μM (95% CI 4.5-102 μM), minimum adhesion inhibitory concentration (MAIC) of 100 μM (40.2 μg/mL). Additionally, allantodapsone inhibited adhesion of Lactococcus lactis strains exogenously expressing the clumping factors to fibrinogen (L. lactis ClfA, IC of 3.8 μM [95% CI 1.0-14.3 μM], MAIC 10 μM, 4.0 μg/mL; and L. lactis ClfB, IC of 11.0 μM [95% CI 0.9-13.6 μM], MAIC 33 μM, 13.3 μg/mL), indicating specific inhibition. Furthermore, the dapsone and alloxan fragments of allantodapsone did not have any inhibitory effect. Adhesion of S. aureus Newman to L2v loricrin is dependent on the expression of ClfB. Allantodapsone caused a dose dependent inhibition of S. aureus adhesion to the L2v loricrin fragment, with full inhibition at 40 μM (OD 0.11 ± 0.01). Furthermore, recombinant ClfB protein binding to L2v loricrin was inhibited by allantodapsone (0.0001). Allantodapsone also demonstrated dose dependent inhibition of S. aureus Newman adhesion to cytokeratin 10 (CK10). Allantodapsone is the first small molecule inhibitor of the S. aureus clumping factors with potential for development as a colonization inhibitor. S. aureus colonization of the nares and the skin provide a reservoir of bacteria that can be transferred to wounds that can ultimately result in systemic infections. Antibiotic resistance can make these infections difficult to treat with significant associated morbidity and mortality. We have identified and characterized a first-in-class small molecule inhibitor of the S. aureus clumping factors A and B, which has the potential to be developed further as a colonization inhibitor.
金黄色葡萄球菌感染由于抗生素耐药性的增加，已成为医疗保健领域的一个主要挑战。我们旨在设计金黄色葡萄球菌表面蛋白的小分子抑制剂，将其开发为定植抑制剂。我们在筛选寻找凝结因子 A 和 B（ClfA 和 ClfB）抑制剂的初步筛选中发现了 allantodapsone。我们使用微生物粘附测定法研究 allantodapsone 对细胞外基质蛋白相互作用的影响。Allantodapsone 以 21.3 μM（95%CI 4.5-102 μM）的 IC 抑制金黄色葡萄球菌 Newman 与纤维蛋白原的粘附，最小粘附抑制浓度（MAIC）为 100 μM（40.2μg/mL）。此外，allantodapsone 抑制了外源表达凝结因子的乳球菌属菌株（乳球菌属 ClfA，IC 为 3.8 μM [95%CI 1.0-14.3 μM]，MAIC 为 10 μM，4.0μg/mL；和乳球菌属 ClfB，IC 为 11.0 μM [95%CI 0.9-13.6 μM]，MAIC 为 33 μM，13.3μg/mL）对纤维蛋白原的粘附，表明其具有特异性抑制作用。此外，dapsone 和 alloxan 片段对 allantodapsone 没有任何抑制作用。金黄色葡萄球菌 Newman 与 L2v 层粘连蛋白的粘附依赖于 ClfB 的表达。Allantodapsone 剂量依赖性抑制金黄色葡萄球菌粘附到 L2v 层粘连蛋白片段，在 40μM（OD 0.11±0.01）时完全抑制。此外，重组 ClfB 蛋白与 L2v 层粘连蛋白的结合也被 allantodapsone 抑制（0.0001）。Allantodapsone 还显示出金黄色葡萄球菌 Newman 对细胞角蛋白 10（CK10）的粘附呈剂量依赖性抑制。Allantodapsone 是金黄色葡萄球菌凝聚因子的第一个小分子抑制剂，具有作为定植抑制剂开发的潜力。金黄色葡萄球菌在鼻腔和皮肤的定植为细菌提供了一个储存库，这些细菌可以转移到伤口，最终导致全身感染。抗生素耐药性使得这些感染难以治疗，相关发病率和死亡率显著增加。我们已经鉴定并表征了金黄色葡萄球菌凝聚因子 A 和 B 的第一个同类小分子抑制剂，它有可能进一步开发为定植抑制剂。
