Inhibitors targeting BamA in gram-negative bacteria

Antibiotic resistance has led to an increase in the number of patient hospitalizations and deaths. The situation for gram-negative bacteria is especially dire as the last new class of antibiotics active against these bacteria was introduced to the clinic over 60 years ago, thus there is an immediate unmet need for new antibiotic classes able to overcome resistance. The outer membrane, a unique and essential structure in gram-negative bacteria, contains multiple potential antibacterial targets including BamA, an outer membrane protein that folds and inserts transmembrane β-barrel proteins. BamA is essential and conserved, and its outer membrane location eliminates a barrier that molecules must overcome to access this target. Recently, antibacterial small molecules, natural products, peptides, and antibodies that inhibit BamA activity have been reported, validating the druggability of this target and generating potential leads for antibiotic development. This review will describe these BamA inhibitors, highlight their key attributes, and identify challenges with this potential target. •Transmembrane β-barrel proteins in gram-negative bacterial outer membranes are folded and inserted by the BAM complex•BamA, the central and essential component of the BAM complex, is a potential gram-negative-specific antibacterial target•Small molecules, antibodies, peptides, and natural products that inhibit BAM highlight the druggability of this target•Additional discovery and optimization efforts will be required to move a BamA inhibitor into clinical development