The recent emergence and rapid dissemination of highly resistant bacterial strains represents an immediate global health concern. Despite the availability of genomic information, the search for new classes of antibiotics has been disappointing and most major pharmaceutical companies have now downsized or eliminated their antibiotic discovery programs. β-Lactams remain the most commonly prescribed antibiotic class, with the carbapenem subgroup representing the most potent of these clinically indispensable agents. Bacteria achieve resistance to β-lactams and carbapenems through the production of β-lactamases and carbapenemases, respectively, coupled, in the case of Gram-negative pathogens, by outer membrane permeability barriers, efflux, and target modifications. While one solution to the problem is the co-administration of a β-lactamase inhibitor, together with the β-lactam antibiotic, the Buynak group has explored an alternative approach of generating carbapenem antibiotics which are themselves poor substrates and/or inhibitors of these bacterial hydrolases. While current carbapenem antibiotics are simple C2 variants of a common scaffold, we have explored more substantial modifications, involving the C1, C5, and C6 position, and successfully reported modifications which improve carbapenemase stability and outer membrane penetration. We will describe the stereospecific synthetic procedures employed to generate these modifications.

Design and stereospecific synthesis of atypical C1, C5, and C6-substituted carbapenem antibiotics

2019 Fall National Meeting

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