Ling Zhuoren, Farley Alistair James Macdonald, Lankapalli Aditya, Zhang Yanfang, Premchand-Branker Shonnette, Cook Kate, Baran Andrei, Gray-Hammerton Charlotte, Orbegozo Rubio Claudia, Suna Edgars, Mathias Jordan, Brem Jürgen, Sands Kirsty, Nieto-Rosado Maria, Trush Maria Mykolaivna, Rakhi Nadira Naznin, Martins Willames, Zhou Yuqing, Schofield Christopher Joseph, Walsh Timothy
Department of Biology & Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3RE, UK.
Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UK.
Engineering (Beijing). 2024 Jul;38:124-132. doi: 10.1016/j.eng.2024.02.010.
This work explores the potential of a triple combination of meropenem (MEM), a novel metallo-β-lactamase (MBL) inhibitor (indole-2-carboxylate 58 (InC58)), and a serine-β-lactamase (SBL) inhibitor (avibactam (AVI)) for broad-spectrum activity against carbapenemase-producing bacteria. A diverse panel comprising MBL- and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution method. The frequency of resistance (FoR) to MEM combined with InC58 was investigated. Mutants were sequenced and tested for cross resistance, fitness, and the stability of the resistance phenotype. Compared with the double combinations of MEM plus an SBL or MBL inhibitor, the triple combination extended the spectrum of activity to most of the isolates bearing SBLs (oxacillinase-48 (OXA-48) and carbapenemase-2 (KPC-2)) and MBLs (New Delhi metallo-β-lactamases (NDMs)), although it was not effective against Verona integron-encoded metallo-β-lactamase (VIM)-carrying () and OXA-23-carrying (). The FoR to MEM plus InC58 ranged from 2.22 × 10 to 1.13 × 10. The resistance correlated with mutations to and , affecting porin C and copper permeability, respectively. The mutants manifested a fitness cost, a decreased level of resistance during passage without antibiotic pressure, and cross resistance to another carbapenem (imipenem) and a β-lactamase inhibitor (taniborbactam). In conclusion, compared with the dual combinations, the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemase-producing bacteria, revealing a new strategy to combat β-lactamase-mediated antimicrobial resistance.
本研究探讨了美罗培南（MEM）、新型金属β-内酰胺酶（MBL）抑制剂（吲哚-2-羧酸酯58（InC58））和丝氨酸β-内酰胺酶（SBL）抑制剂（阿维巴坦（AVI））三联组合对产碳青霉烯酶细菌的广谱抗菌活性。使用琼脂稀释法，对一组包含产MBL和SBL菌株的不同菌株进行三联组合的药敏试验。研究了MEM联合InC58的耐药频率（FoR）。对突变体进行测序，并检测其交叉耐药性、适应性和耐药表型的稳定性。与MEM加SBL或MBL抑制剂的双联组合相比，三联组合将活性谱扩展至大多数携带SBL（奥克西林酶-48（OXA-48）和碳青霉烯酶-2（KPC-2））和MBL（新德里金属β-内酰胺酶（NDM））的分离株，尽管它对携带维罗纳整合子编码金属β-内酰胺酶（VIM）的菌株（）和携带OXA-23的菌株（）无效。MEM加InC58的FoR范围为2.22×10至1.13×10。耐药性分别与和的突变相关，这些突变分别影响孔蛋白C和铜通透性。突变体表现出适应性代价，在无抗生素压力传代过程中耐药水平降低，并且对另一种碳青霉烯类药物（亚胺培南）和一种β-内酰胺酶抑制剂（他尼硼巴坦）具有交叉耐药性。总之，与双联组合相比，MEM与InC58和AVI的三联组合对不同产碳青霉烯酶细菌显示出更广泛的活性谱，揭示了一种对抗β-内酰胺酶介导的抗菌药物耐药性的新策略。
