David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.
M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Antimicrob Agents Chemother. 2024 Sep 4;68(9):e0027224. doi: 10.1128/aac.00272-24. Epub 2024 Aug 12.
The effectiveness of β-lactam antibiotics is increasingly threatened by resistant bacteria that harbor hydrolytic β-lactamase enzymes. Depending on the class of β-lactamase present, β-lactam hydrolysis can occur through one of two general molecular mechanisms. Metallo-β-lactamases (MBLs) require active site Zn ions, whereas serine-β-lactamases (SBLs) deploy a catalytic serine residue. The result in both cases is drug inactivation via the opening of the β-lactam warhead of the antibiotic. MBLs confer resistance to most β-lactams and are non-susceptible to SBL inhibitors, including recently approved diazabicyclooctanes, such as avibactam; consequently, these enzymes represent a growing threat to public health. Aspergillomarasmine A (AMA), a fungal natural product, can rescue the activity of the β-lactam antibiotic meropenem against MBL-expressing bacterial strains. However, the effectiveness of this β-lactam/β-lactamase inhibitor combination against bacteria producing multiple β-lactamases remains unknown. We systematically investigated the efficacy of AMA/meropenem combination therapy with and without avibactam against 10 and 10 laboratory strains tandemly expressing single MBL and SBL enzymes. Cell-based assays demonstrated that laboratory strains producing NDM-1 and KPC-2 carbapenemases were resistant to the AMA/meropenem combination but became drug-susceptible upon adding avibactam. We also probed these combinations against 30 clinical isolates expressing multiple β-lactamases. , and clinical isolates were more susceptible to AMA, avibactam, and meropenem than and isolates. Overall, the results demonstrate that a triple combination of AMA/avibactam/meropenem has potential for empirical treatment of infections caused by multiple β-lactamase-producing bacteria, especially Enterobacterales.
β-内酰胺类抗生素的有效性日益受到携带水解β-内酰胺酶的耐药菌的威胁。根据存在的β-内酰胺酶的类别，β-内酰胺的水解可以通过两种一般的分子机制之一发生。金属β-内酰胺酶（MBLs）需要活性位点 Zn 离子，而丝氨酸β-内酰胺酶（SBLs）则利用催化丝氨酸残基。在这两种情况下，结果都是通过抗生素的β-内酰胺弹头的打开使药物失活。MBLs 使大多数β-内酰胺类药物产生耐药性，并且对 SBL 抑制剂（包括最近批准的二氮杂双环辛烷，如阿维巴坦）不敏感；因此，这些酶对公共卫生构成了日益严重的威胁。曲霉马马雷素 A（AMA），一种真菌天然产物，可以恢复β-内酰胺类抗生素美罗培南对表达 MBL 的细菌菌株的活性。然而，这种β-内酰胺/β-内酰胺酶抑制剂联合对产生多种β-内酰胺酶的细菌的有效性尚不清楚。我们系统地研究了 AMA/美罗培南联合治疗与不加用阿维巴坦治疗 10 株和 10 株串联表达单一 MBL 和 SBL 酶的实验室菌株的疗效。基于细胞的测定表明，产生 NDM-1 和 KPC-2 碳青霉烯酶的实验室菌株对 AMA/美罗培南联合治疗具有耐药性，但加入阿维巴坦后变为药物敏感。我们还针对 30 株表达多种β-内酰胺酶的临床分离株探测了这些组合。与 和 临床分离株相比， 、 和 临床分离株对 AMA、阿维巴坦和美罗培南更敏感。总体而言，结果表明，AMA/阿维巴坦/美罗培南三联组合具有治疗多种β-内酰胺酶产生菌感染的潜力，特别是肠杆菌科感染。
