Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Centergrid.412807.8, Nashville, Tennessee, USA.
Department of Pathobiological Sciences, Louisiana State Universitygrid.64337.35 and Agricultural and Mechanical College, School of Veterinary Medicine, Baton Rouge, Louisiana, USA.
Microbiol Spectr. 2022 Apr 27;10(2):e0276721. doi: 10.1128/spectrum.02767-21. Epub 2022 Apr 4.
Aminoglycoside antibiotics rely on the proton motive force to enter the bacterial cell, and facultative anaerobes like Staphylococcus aureus can shift energy generation from respiration to fermentation, becoming tolerant of aminoglycosides. Following this metabolic shift, high concentrations of aminoglycosides are required to eradicate S. aureus infections, which endangers the host due to the toxicity of aminoglycosides. Membrane-disrupting molecules prevent aminoglycoside tolerance in S. aureus by facilitating passive entry of the drug through the membrane. Polyunsaturated fatty acids (PUFAs) increase membrane permeability when incorporated into S. aureus. Here, we report that the abundant host-derived PUFA arachidonic acid increases the susceptibility of S. aureus to aminoglycosides, decreasing the aminoglycoside concentration needed to kill S. aureus. We demonstrate that PUFAs and aminoglycosides synergize to kill multiple strains of S. aureus, including both methicillin-resistant and -susceptible S. aureus. We also present data showing that PUFAs and aminoglycosides effectively kill S. aureus small colony variants, strains that are particularly recalcitrant to killing by many antibiotics. We conclude that cotreatment with PUFAs, which are molecules with low host toxicity, and aminoglycosides decreases the aminoglycoside concentration necessary to kill S. aureus, lowering the toxic side effects to the host associated with prolonged aminoglycoside exposure. Staphylococcus aureus infects every niche of the human host, and these infections are the leading cause of Gram-positive sepsis. Aminoglycoside antibiotics are inexpensive, stable, and effective against many bacterial infections. However, S. aureus can shift its metabolism to become tolerant of aminoglycosides, requiring increased concentrations and/or longer courses of treatment, which can cause severe host toxicity. Here, we report that polyunsaturated fatty acids (PUFAs), which have low host toxicity, disrupt the S. aureus membrane, making the pathogen susceptible to aminoglycosides. Additionally, cotreatment with aminoglycosides is effective at killing S. aureus small colony variants, strains that are difficult to treat with antibiotics. Taken together, the data presented herein show the promise of PUFA cotreatment to increase the efficacy of aminoglycosides against S. aureus infections and decrease the risk to the human host of antibiotic-induced toxicity.
氨基糖苷类抗生素依赖质子动力进入细菌细胞，而金黄色葡萄球菌等兼性厌氧菌可以将能量生成从呼吸转变为发酵，从而对氨基糖苷类药物产生耐受性。在这种代谢转变之后，需要高浓度的氨基糖苷类药物来消灭金黄色葡萄球菌感染，这会由于氨基糖苷类药物的毒性而危及宿主。通过破坏细胞膜的分子促进药物被动进入膜内，从而防止金黄色葡萄球菌产生氨基糖苷类药物耐受性。多不饱和脂肪酸（PUFAs）在掺入金黄色葡萄球菌时会增加细胞膜的通透性。在这里，我们报告说，丰富的宿主衍生的多不饱和脂肪酸花生四烯酸会增加金黄色葡萄球菌对氨基糖苷类药物的敏感性，从而降低杀死金黄色葡萄球菌所需的氨基糖苷类药物浓度。我们证明 PUFAs 和氨基糖苷类药物协同作用可杀死多种金黄色葡萄球菌，包括耐甲氧西林和敏感的金黄色葡萄球菌。我们还提供的数据表明，PUFAs 和氨基糖苷类药物可有效杀死金黄色葡萄球菌小菌落变异株，这些菌株特别难以被许多抗生素杀死。我们得出的结论是，用 PUFAs 与氨基糖苷类药物联合治疗可降低杀死金黄色葡萄球菌所需的氨基糖苷类药物浓度，从而降低与延长氨基糖苷类药物暴露相关的宿主毒性的副作用。金黄色葡萄球菌感染人体的每个部位，这些感染是革兰氏阳性菌败血症的主要原因。氨基糖苷类抗生素价格低廉、稳定且对许多细菌感染有效。然而，金黄色葡萄球菌可以改变其代谢方式以产生对氨基糖苷类药物的耐受性，这需要增加浓度和/或延长治疗时间，这可能会导致严重的宿主毒性。在这里，我们报告说，多不饱和脂肪酸（PUFAs）具有低宿主毒性，可破坏金黄色葡萄球菌的细胞膜，使病原体对氨基糖苷类药物敏感。此外，氨基糖苷类药物的联合治疗对杀死金黄色葡萄球菌小菌落变异株有效，这些菌株很难用抗生素治疗。综上所述，本文提供的数据表明，PUFA 联合治疗有望提高氨基糖苷类药物对金黄色葡萄球菌感染的疗效，并降低抗生素诱导的毒性对人类宿主的风险。
