Department of Biology, University of York, York, United Kingdom.
Department of Mathematics, University of York, York, United Kingdom.
Microbiol Spectr. 2022 Dec 21;10(6):e0184222. doi: 10.1128/spectrum.01842-22. Epub 2022 Dec 1.
The Pseudomonas aeruginosa bacterium is a common pathogen of cystic fibrosis (CF) patients due to its ability to evolve resistance to antibiotics during treatments. While P. aeruginosa resistance evolution is well-characterized in monocultures, it is less well-understood in polymicrobial CF infections. Here, we investigated how exposure to ciprofloxacin, colistin, or tobramycin antibiotics, administered at sub-minimum inhibitory concentration (MIC) doses, both alone and in combination, shaped the tolerance evolution of P. aeruginosa (PAO1 lab and clinical CF LESB58 strains) in the absence and presence of a commonly co-occurring species, Stenotrophomonas maltophilia. The increases in antibiotic tolerances were primarily driven by the presence of that antibiotic in the treatment. We observed a reciprocal cross-tolerance between ciprofloxacin and tobramycin, and, when combined, the selected antibiotics increased the MICs for all of the antibiotics. Though the presence of S. maltophilia did not affect the tolerance or the MIC evolution, it drove P. aeruginosa into extinction more frequently in the presence of tobramycin due to its relatively greater innate tobramycin tolerance. In contrast, P. aeruginosa dominated and drove S. maltophilia extinct in most other treatments. Together, our findings suggest that besides driving high-level antibiotic tolerance evolution, sub-MIC antibiotic exposure can alter competitive bacterial interactions, leading to target pathogen extinctions in multispecies communities. Cystic fibrosis (CF) is a genetic condition that results in thick mucus secretions in the lungs that are susceptible to chronic bacterial infections. The bacterial pathogen Pseudomonas aeruginosa is often associated with morbidity in CF and is difficult to treat due to its high resistance to antibiotics. The resistance evolution of Pseudomonas aeruginosa is poorly understood in polymicrobial infections that are typical of CF. To study this, we exposed P. aeruginosa to sublethal concentrations of ciprofloxacin, colistin, or tobramycin antibiotics in the absence and presence of a commonly co-occurring CF species, Stenotrophomonas maltophilia. We found that low-level antibiotic concentrations selected for high-level antibiotic resistance. While P. aeruginosa dominated in most antibiotic treatments, S. maltophilia drove it into extinction in the presence of tobramycin due to an innately higher tobramycin resistance. Our findings suggest that, besides driving high-level antibiotic tolerance evolution, sublethal antibiotic exposure can magnify competition in bacterial communities, which can lead to target pathogen extinctions in multispecies communities.
铜绿假单胞菌是囊性纤维化 (CF) 患者的常见病原体，因为它在治疗过程中能够对抗生素产生耐药性。虽然铜绿假单胞菌在单一培养物中的耐药性进化已得到很好的描述，但在多微生物 CF 感染中的耐药性进化却知之甚少。在这里，我们研究了在不存在和存在一种常见共生病原菌嗜麦芽寡养单胞菌的情况下，亚最低抑菌浓度 (MIC) 剂量的环丙沙星、多粘菌素或妥布霉素单独或联合使用时，铜绿假单胞菌 (PAO1 实验室和临床 CF LESB58 菌株) 的耐受力进化情况。抗生素耐受力的增加主要是由于治疗中存在该抗生素。我们观察到环丙沙星和妥布霉素之间存在交叉耐药性，并且当联合使用时，所选抗生素会增加所有抗生素的 MIC。尽管嗜麦芽寡养单胞菌的存在不会影响耐受力或 MIC 进化，但由于其对妥布霉素的固有较高耐受力，它在妥布霉素存在的情况下更频繁地导致铜绿假单胞菌灭绝。相比之下，铜绿假单胞菌在大多数其他治疗中占主导地位，并导致嗜麦芽寡养单胞菌灭绝。总的来说，我们的发现表明，除了推动高水平抗生素耐药性进化外，亚 MIC 抗生素暴露还可以改变竞争细菌相互作用，导致多物种群落中目标病原体灭绝。囊性纤维化 (CF) 是一种遗传疾病，导致肺部产生浓稠的粘液分泌物，容易受到慢性细菌感染。铜绿假单胞菌是 CF 中常与发病率相关的细菌病原体，由于其对抗生素的高度耐药性，因此难以治疗。铜绿假单胞菌在多微生物感染中的耐药性进化在 CF 中很常见，但了解甚少。为了研究这一点，我们在不存在和存在一种常见的 CF 共生菌嗜麦芽寡养单胞菌的情况下，将铜绿假单胞菌暴露于亚致死浓度的环丙沙星、多粘菌素或妥布霉素抗生素中。我们发现，低水平的抗生素浓度选择了高水平的抗生素耐药性。虽然铜绿假单胞菌在大多数抗生素治疗中占主导地位，但由于其对妥布霉素的固有更高耐药性，在妥布霉素存在的情况下，嗜麦芽寡养单胞菌将其推向灭绝。我们的发现表明，除了推动高水平抗生素耐药性进化外，亚致死抗生素暴露还可以放大细菌群落中的竞争，这可能导致多物种群落中的目标病原体灭绝。
