GangaGen Biotechnologies Pvt Ltd., Yeshwantpur, Bangalore, India.
GangaGen Biotechnologies Pvt Ltd., Yeshwantpur, Bangalore, India
Antimicrob Agents Chemother. 2017 Jul 25;61(8). doi: 10.1128/AAC.00457-17. Print 2017 Aug.
Coagulase-negative staphylococci (CoNS) are the major causative agents of foreign-body-related infections, including catheter-related bloodstream infections. Because of the involvement of biofilms, foreign-body-related infections are difficult to treat. P128, a chimeric recombinant phage-derived ectolysin, has been shown to possess bactericidal activity on strains of , including methicillin-resistant (MRSA). We tested the killing potential of P128 on three clinically significant species of CoNS, , , and , under a variety of physiological conditions representing growing and nongrowing states. The MIC and minimum bactericidal concentration at which 90% of strains tested are killed (MBC) of P128 on 62 clinical strains of CoNS were found to be 16 and 32 μg/ml (0.58 and 1.16 μM), respectively, demonstrating the bactericidal nature of P128 on CoNS strains. Serum showed a potentiating effect on P128 inhibition, as indicated by 4- to 32-fold lower MIC values observed in serum. P128 caused a rapid loss of viability in all CoNS strains tested. Persisters of CoNS that were enriched in the presence of vancomycin or daptomycin were killed by P128 at 1× the MIC in a rapid manner. Low concentrations of P128 caused a 2- to 5-log reduction in CFU in stationary-phase or poorly metabolizing CoNS cultures. P128 at low concentrations eliminated CoNS biofilms in microtiter plates and on the surface of catheters. Combinations of P128 and standard-of-care (SoC) antibiotics were highly synergistic in inhibiting growth in preformed biofilms. Potent activity on planktonic cells, persisters, and biofilms of CoNS suggests that P128 is a promising candidate for the clinical development of treatments for foreign-body-related and other CoNS infections.
凝固酶阴性葡萄球菌（CoNS）是引起异物相关感染的主要病原体，包括导管相关血流感染。由于生物膜的参与，异物相关感染难以治疗。P128 是一种嵌合重组噬菌体衍生的细胞溶素，已被证明对包括耐甲氧西林金黄色葡萄球菌（MRSA）在内的多种菌株具有杀菌活性。我们在各种生理条件下测试了 P128 对三种临床相关凝固酶阴性葡萄球菌（表皮葡萄球菌、人葡萄球菌和溶血葡萄球菌）的杀菌潜力，这些条件代表了生长和非生长状态。P128 对 62 株临床分离的凝固酶阴性葡萄球菌的 MIC 和能杀死 90%受试菌株的最低杀菌浓度（MBC）分别为 16 和 32μg/ml（0.58 和 1.16μM），表明 P128 对凝固酶阴性葡萄球菌具有杀菌作用。血清对 P128 抑制作用具有增效作用，因为在血清中观察到 MIC 值降低了 4-32 倍。P128 使所有测试的凝固酶阴性葡萄球菌菌株迅速丧失活力。在万古霉素或达托霉素存在下富集的凝固酶阴性葡萄球菌的持续期细胞可被 P128 在 1×MIC 浓度下快速杀死。低浓度的 P128 可使静止期或代谢不良的凝固酶阴性葡萄球菌培养物中的 CFU 减少 2-5 对数级。P128 以低浓度在微量滴定板和导管表面消除凝固酶阴性葡萄球菌生物膜。P128 与标准治疗（SoC）抗生素联合使用对抑制已形成的生物膜中的生长具有高度协同作用。对浮游细胞、持续期细胞和凝固酶阴性葡萄球菌生物膜的强大活性表明，P128 是治疗异物相关和其他凝固酶阴性葡萄球菌感染的有前途的候选药物。
