Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY, United States of America.
Institute of Infectious Diseases and Pathogenic Microbiology, Prienai, Lithuania.
PLoS One. 2024 Mar 22;19(3):e0300380. doi: 10.1371/journal.pone.0300380. eCollection 2024.
Antimicrobial resistance (AMR) represents an alarming global challenge to public health. Infections caused by multidrug-resistant Staphylococcus aureus (S. aureus) pose an emerging global threat. Therefore, it is crucial to develop novel compounds with promising antimicrobial activity against S. aureus especially those with challenging resistance mechanisms and biofilm formation. Series of bis(thiazol-5-yl)phenylmethane derivatives were evaluated against drug-resistant Gram-positive bacteria. The screening revealed an S. aureus-selective mechanism of bis(thiazol-5-yl)phenylmethane derivatives (MIC 2-64 μg/mL), while significantly lower activity was observed with vancomycin-resistant Enterococcus faecalis (MIC 64 μg/mL) (p<0.05). The most active phenylmethane-based (p-tolyl) derivative, 23a, containing nitro and dimethylamine substituents, and the naphthalene-based derivative, 28b, harboring fluorine and nitro substituents, exhibited strong, near MIC bactericidal activity against S. aureus with genetically defined resistance phenotypes such as MSSA, MRSA, and VRSA and their biofilms. The in silico modeling revealed that most promising compounds 23a and 28b were predicted to bind S. aureus MurC ligase. The 23a and 28b formed bonds with MurC residues at binding site, specifically Ser12 and Arg375, indicating consequential interactions essential for complex stability. The in vitro antimicrobial activity of compound 28b was not affected by the addition of 50% serum. Finally, all tested bis(thiazol-5-yl)phenylmethane derivatives showed favorable cytotoxicity profiles in A549 and THP-1-derived macrophage models. These results demonstrated that bis(thiazol-5-yl)phenylmethane derivatives 23a and 28b could be potentially explored as scaffolds for the development of novel candidates targeting drug-resistant S. aureus. Further studies are also warranted to understand in vivo safety, efficacy, and pharmacological bioavailability of bis(thiazol-5-yl)phenylmethane derivatives.
抗菌药物耐药性（AMR）对公共卫生构成了严峻的全球性挑战。耐多药金黄色葡萄球菌（S. aureus）引起的感染构成了新兴的全球威胁。因此，开发具有抗金黄色葡萄球菌活性的新型化合物至关重要，尤其是那些具有挑战性的耐药机制和生物膜形成的化合物。一系列双（噻唑-5-基）苯甲烷衍生物被评估了对耐药革兰氏阳性菌的抗菌活性。筛选结果表明，双（噻唑-5-基）苯甲烷衍生物具有针对金黄色葡萄球菌的选择性作用机制（MIC 2-64 μg/mL），而对万古霉素耐药粪肠球菌的活性显著降低（MIC 64 μg/mL）（p<0.05）。含硝基和二甲胺取代基的基于苯甲烷的最活跃（对甲苯基）衍生物 23a 和含氟和硝基取代基的基于萘的衍生物 28b 对金黄色葡萄球菌表现出强大的、接近 MIC 的杀菌活性，对具有遗传定义的耐药表型（如 MSSA、MRSA 和 VRSA）及其生物膜也有杀菌活性。基于计算机的建模显示，最有前途的化合物 23a 和 28b 被预测与金黄色葡萄球菌 MurC 连接酶结合。化合物 23a 和 28b 在结合部位与 MurC 残基形成键，特别是 Ser12 和 Arg375，表明对复合物稳定性至关重要的后续相互作用。化合物 28b 的体外抗菌活性不受添加 50%血清的影响。最后，所有测试的双（噻唑-5-基）苯甲烷衍生物在 A549 和 THP-1 衍生的巨噬细胞模型中均显示出良好的细胞毒性特征。这些结果表明，双（噻唑-5-基）苯甲烷衍生物 23a 和 28b 可能作为开发针对耐药金黄色葡萄球菌的新型候选药物的潜在骨架。还需要进一步研究以了解双（噻唑-5-基）苯甲烷衍生物的体内安全性、疗效和药物生物利用度。
