“One-Two Punch”: Synergistic ß-Lactam Combinations for<i>Mycobacterium abscessus</i>and Target Redundancy in the Inhibition of Peptidoglycan Synthesis Enzymes
David C. Nguyen, Khalid M Dousa, Sebastian G. Kurz, Sheldon T. Brown, George L. Drusano, Steven M. Holland, Barry N. Kreiswirth, W. Henry Boom, Charles L. Daley, Robert A. Bonomo
Abstract
Mycobacterium abscessus subsp. abscessus is one of the most difficult pathogens to treat and its incidence in disease is increasing. Dual β-lactam combinations act synergistically in vitro but are not widely employed in practice. A recent study shows that a combination of imipenem and ceftaroline significantly lowers the minimum inhibitory concentration of clinical isolates, despite both drugs targeting the same peptidoglycan synthesis enzymes. The underlying mechanism of this effect provides a basis for further investigations of dual β-lactam combinations in the treatment of M. abscessus subsp. abscessus, eventually leading to a clinical trial. Furthermore, dual β-lactam strategies may be explored for other difficult mycobacterial infections.