Hall Kalen M, Williams Leonard G, Smith Richard D, Kuang Erin A, Ernst Robert K, Bojanowski Christine M, Wimley William C, Morici Lisa A, Pursell Zachary F
Department of Microbiology and Immunology, School of Medicine, Tulane University, New Orleans, LA, USA.
Department of Biochemistry and Molecular Biology, School of Medicine, Tulane University, New Orleans, LA, USA.
Nat Commun. 2025 Jan 2;16(1):19. doi: 10.1038/s41467-024-55206-w.
Bacteria of clinical importance, such as Pseudomonas aeruginosa, can become hypermutators upon loss of DNA mismatch repair (MMR) and are clinically correlated with high rates of multidrug resistance (MDR). Here, we demonstrate that hypermutated MMR-deficient P. aeruginosa has a unique mutational signature and rapidly acquires MDR upon repeated exposure to first-line or last-resort antibiotics. MDR acquisition was irrespective of drug class and instead arose through common resistance mechanisms shared between the initial and secondary drugs. Rational combinations of drugs having distinct resistance mechanisms prevented MDR acquisition in hypermutated MMR-deficient P. aeruginosa. Mutational signature analysis of P. aeruginosa across different human disease contexts identified appreciable quantities of MMR-deficient clinical isolates that were already MDR or prone to future MDR acquisition. Mutational signature analysis of patient samples is a promising diagnostic tool that may predict MDR and guide precision-based medical care.
具有临床重要性的细菌，如铜绿假单胞菌，在失去DNA错配修复（MMR）后可成为超突变体，并在临床上与高多重耐药率（MDR）相关。在这里，我们证明超突变的MMR缺陷型铜绿假单胞菌具有独特的突变特征，并且在反复接触一线或最后手段抗生素后会迅速获得MDR。MDR的获得与药物类别无关，而是通过初始药物和二次药物之间共有的常见耐药机制产生的。具有不同耐药机制的药物的合理组合可防止超突变的MMR缺陷型铜绿假单胞菌获得MDR。对不同人类疾病背景下的铜绿假单胞菌进行突变特征分析，发现有相当数量的MMR缺陷型临床分离株已经是MDR或易于在未来获得MDR。对患者样本进行突变特征分析是一种很有前景的诊断工具，可预测MDR并指导基于精准的医疗护理。
