Multidrug resistant Acinetobacter baumannii (MDRAb) constitutes a serious nosocomial pathogen with a high mortality rate. MDRAb resistance to the carbapenem antibiotics, representing a last-line therapy for such serious pathogens, is achieved through production of one or more carbapenemases, particularly including the carbapenem-hydrolyzing class D beta-lactamases (CHDLs) such as OXA-23, but increasingly including metallo-carbapenemases, such as NDM and VIM. Carbapenem antibiotics were optimized in the 20th century to achieve broad spectrum activity against pathogens of that era, and structural modifications over the past 40 years have focused on the 2-position. The Buynak group is exploring atypical (i.e. non-C2) structural carbapenem modifications, and, now, in collaboration with the Vakulenko group, has discovered that one such atypical structural modification imparts, metallo-carbapenemase stability, in addition to CHDL stability. Methods: Atypically substituted carbapenem antibiotics were prepared and evaluated, relative to meropenem, against strains of A. baumannii producing OXA-23, OXA-48, KPC-6, GES-5, NDM-1, VIM-2, ADC-1 and TEM-1. Results: One new carbapenem displayed exceptional activity, with MICs in the range of 2-4 mg/L against all strains, representing improvements from 4-&gt;128-fold over meropenem, including a 64-fold and 16-fold improvement, relative to meropenem, against Ab strains producing NDM-1 and VIM-2, respectively. Conclusions: It is time to challenge the presumption that the carbapenem scaffold has been optimized, particularly with respect to activity against 21st century pathogens.

Carbapenemase-stable carbapenem antibiotics with potential to treat multidrug-resistant acinetobacter baumannii

ACS Fall 2020 Virtual Meeting

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