Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
ISME J. 2022 Jul;16(7):1694-1704. doi: 10.1038/s41396-022-01218-7. Epub 2022 Mar 19.
The airways of people with cystic fibrosis (CF) often harbour diverse polymicrobial communities. These airway infections can be impossible to resolve through antibiotic intervention, even though isolates of the individual species present are susceptible to the treatment when tested in vitro. In this work, we investigate how polymicrobial cultures comprised of key CF-associated pathogens respond to challenge with species-specific antimicrobial agents; colistin (targets Pseudomonas aeruginosa), fusidic acid (targets Staphylococcus aureus), and fluconazole (targets Candida albicans). We found that growth in a polymicrobial environment protects the target microorganism (sometimes by several orders of magnitude) from the effect(s) of the antimicrobial agent. This decreased antimicrobial efficacy was found to have both non-heritable (physiological) and heritable (genetic) components. Whole-genome sequencing of the colistin-resistant P. aeruginosa isolates revealed single nucleotide polymorphisms and indels in genes encoding lipopolysaccharide (LPS) biosynthesis and/or pilus biogenesis, indicating that a previously undescribed colistin resistance mechanism was in operation. This was subsequently confirmed through further genetic analyses. Our findings indicate that the polymicrobial nature of the CF airways is likely to have a significant impact on the clinical response to antimicrobial therapy.
囊性纤维化（CF）患者的气道通常存在多种多微生物群落。尽管体外测试时，个体物种的分离物对治疗敏感，但这些气道感染仍然无法通过抗生素干预来解决。在这项工作中，我们研究了由关键 CF 相关病原体组成的多微生物培养物如何对针对特定物种的抗菌剂（多粘菌素（针对铜绿假单胞菌）、夫西地酸（针对金黄色葡萄球菌）和氟康唑（针对白色念珠菌））的挑战作出反应；我们发现，在多微生物环境中生长可以保护目标微生物（有时多达几个数量级）免受抗菌剂的影响。这种抗菌效果的降低既有非遗传性（生理）的，也有遗传性（遗传）的成分。对耐多粘菌素的铜绿假单胞菌分离株进行全基因组测序发现，编码脂多糖（LPS）生物合成和/或菌毛生物发生的基因中存在单核苷酸多态性和插入/缺失，表明存在一种以前未描述的多粘菌素耐药机制。这随后通过进一步的遗传分析得到了证实。我们的研究结果表明，CF 气道的多微生物性质可能对抗菌治疗的临床反应有重大影响。
