Routes of Synthesis of Carbapenems for Optimizing Both the Inactivation of L,D-Transpeptidase LdtMt1 of Mycobacterium tuberculosis and the Stability toward Hydrolysis by β-Lactamase BlaC

Combinations of beta-lactams of the carbapenem class, such as meropenem, with clavulanate, a beta-lactamase inhibitor, are being evaluated for the treatment of drug resistant tuberculosis. However, carbapenems approved for human use have never been optimized for inactivation of the unusual beta-lactam targets of Mycobacterium tuberculosis or for escaping to hydrolysis by broad-spectrum beta-lactamase BlaC. Here, we report three routes of synthesis for modification of the two side chains carried by the beta-lactam and the five-membered rings of the carbapenem core. In particular, we show that the azide-alkyne Huisgen cycloaddition reaction catalyzed by copper(I) is fully compatible with the highly unstable beta-lactam ring of carbapenems and that the triazole ring generated by this reaction is well tolerated for inactivation of the L,D-transpeptidase Ldt(Mt1) target. Several of our new carbapenems are superior to meropenem both with respect to the efficiency of in vitro inactivation of Ldt(Mt1) and reduced hydrolysis by BlaC.