The Role of β-Lactam Antibiotics in Treating Mycobacterium abscessus: From Laboratory Insights to Clinical Applications and the Case for Clinical Trials

Mycobacterium abscessus (Mab) is a highly drug-resistant non-tuberculous mycobacterium that presents major treatment challenges, particularly in individuals with structural lung disease. Although historically considered ineffective, β-lactam antibiotics have gained renewed attention due to advances in β-lactamase inhibition and cell wall biology. This review synthesizes more than a decade of work, including in vitro susceptibility studies, biochemical characterization of Mab's β-lactamase (Bla_Mab) and peptidoglycans synthesis, and published clinical cases supporting the potential role of β-lactam-based regimens. We detail the enzymatic pathways involved in peptidoglycan cross-linking and the dual inhibition of D,D- and L,D-transpeptidases by select β-lactams, as well as the functional impact of inhibiting Bla_Mab. Novel β-lactamase inhibitors such as durlobactam may further enhance β-lactam efficacy. By integrating laboratory insights with clinical experience, this review provides a comprehensive perspective and informs ongoing efforts to design clinical trials repurposing β-lactam/β-lactamase inhibitor combinations.