Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru 560064, India.
J Med Chem. 2015 Jul 23;58(14):5486-500. doi: 10.1021/acs.jmedchem.5b00443. Epub 2015 Jul 9.
Treating bacterial biofilms with conventional antibiotics is limited due to ineffectiveness of the drugs and higher propensity to develop bacterial resistance. Development of new classes of antibacterial therapeutics with alternative mechanisms of action has become imperative. Herein, we report the design, synthesis, and biological evaluations of novel membrane-active small molecules featuring two positive charges, four nonpeptidic amide groups, and variable hydrophobic/hydrophilic (amphiphilic) character. The biocides synthesized via a facile methodology not only displayed good antibacterial activity against wild-type bacteria but also showed high activity against various drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and β-lactam-resistant Klebsiella pneumoniae. Further, these biocides not only inhibited the formation of biofilms but also disrupted the established S. aureus and E. coli biofilms. The membrane-active biocides hindered the propensity to develop bacterial resistance. Moreover, the biocides showed negligible toxicity against mammalian cells and thus bear potential to be used as therapeutic agents.
由于传统抗生素的药物效果不佳，且更容易产生细菌耐药性，因此用其治疗细菌生物膜受到限制。开发具有不同作用机制的新型抗菌治疗药物已成为当务之急。在此，我们报告了具有两个正电荷、四个非肽酰胺基团和可变疏水性/亲水性（两亲性）特征的新型膜活性小分子的设计、合成和生物学评估。通过简便的方法合成的杀菌剂不仅对野生型细菌表现出良好的抗菌活性，而且对各种耐药菌如耐甲氧西林金黄色葡萄球菌（MRSA）、万古霉素耐药粪肠球菌（VRE）和β-内酰胺耐药肺炎克雷伯菌也表现出高活性。此外，这些杀菌剂不仅抑制生物膜的形成，而且还破坏了已建立的金黄色葡萄球菌和大肠杆菌生物膜。膜活性杀菌剂抑制了细菌产生耐药性的倾向。此外，杀菌剂对哺乳动物细胞的毒性可忽略不计，因此具有作为治疗剂的潜力。
