Wijers Christiaan D M, Pham Ly, Douglass Martin V, Skaar Eric P, Palmer Lauren D, Noto Michael J
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, United States.
Department of Microbiology and Immunology, University of Illinois Chicago, 835 South Wolcott Avenue, Chicago, IL 60612, United States.
FEMS Microbes. 2022 May 13;3:xtac016. doi: 10.1093/femsmc/xtac016. eCollection 2022.
exposure of multiple Gram-negative bacteria to an aminoglycoside (AG) antibiotic has previously been demonstrated to result in bacterial alterations that interact with host factors to suppress Gram-negative pneumonia. However, the mechanisms resulting in suppression are not known. Here, the hypothesis that Gram-negative bacteria bind and retain AGs, which are introduced into the lung and interact with host defenses to affect bacterial killing, was tested. Following exposure of one of several, pathogenic Gram-negative bacteria to the AG antibiotics kanamycin or gentamicin, AGs were detected in bacterial cell pellets (up to 208 μg/mL). Using inhibitors of AG binding and internalization, the bacterial outer membrane was implicated as the predominant kanamycin and gentamicin reservoir. Following intranasal administration of gentamicin-bound bacteria or gentamicin solution at the time of infection with live, AG-naïve bacteria, gentamicin was detected in the lungs of infected mice (up to 8 μg/g). Co-inoculation with gentamicin-bound bacteria resulted in killing of AG-naïve bacteria by up to 3-log, mirroring the effects of intranasal gentamicin treatment. killing of AG-naïve bacteria mediated by kanamycin-bound bacteria required the presence of detergents or pulmonary surfactant, suggesting that increased bacterial killing inside the murine lung is facilitated by the detergent component of pulmonary surfactant. These findings demonstrate that Gram-negative bacteria bind and retain AGs that can interact with host-derived pulmonary surfactant to enhance bacterial killing in the lung. This may help explain why AGs appear to have unique efficacy in the lung and might expand their clinical utility.
先前已证明，多种革兰氏阴性菌暴露于氨基糖苷类（AG）抗生素会导致细菌发生改变，这些改变与宿主因素相互作用，从而抑制革兰氏阴性菌肺炎。然而，导致抑制的机制尚不清楚。在此，我们测试了这样一种假设：革兰氏阴性菌结合并保留引入肺部的AG，AG与宿主防御相互作用，从而影响细菌的杀灭。在几种致病性革兰氏阴性菌之一暴露于AG抗生素卡那霉素或庆大霉素后，在细菌细胞沉淀中检测到了AG（高达208μg/mL）。使用AG结合和内化抑制剂，发现细菌外膜是卡那霉素和庆大霉素的主要储存部位。在用未接触过AG的活细菌感染时，经鼻给予结合庆大霉素的细菌或庆大霉素溶液后，在感染小鼠的肺部检测到了庆大霉素（高达8μg/g）。与结合庆大霉素的细菌共同接种导致未接触过AG的细菌杀灭率高达3个对数级，这与经鼻给予庆大霉素治疗的效果相似。由结合卡那霉素的细菌介导的未接触过AG的细菌杀灭需要洗涤剂或肺表面活性剂的存在，这表明肺表面活性剂的洗涤剂成分促进了小鼠肺内细菌杀灭的增加。这些发现表明，革兰氏阴性菌结合并保留AG，AG可与宿主来源的肺表面活性剂相互作用，从而增强肺内细菌的杀灭。这可能有助于解释为什么AG在肺部似乎具有独特的疗效，并可能扩大其临床应用。
