β-Barrel Assembly Machinery (BAM) Complex as Novel Antibacterial Drug Target

Abstract

The outer membrane of Gram-negative bacteria is closely related to the pathogenicity and drug resistance of bacteria. Outer membrane proteins (OMPs) are a class of proteins with important biological functions on the outer membrane. The β-barrel assembly machinery (BAM) complex plays a key role in OMP biogenesis, which ensures that the OMP is inserted into the outer membrane in a correct folding manner and performs nutrient uptake, antibiotic resistance, cell adhesion, cell signaling, and maintenance of membrane stability and other functions. The BAM complex is highly conserved among Gram-negative bacteria. The abnormality of the BAM complex will lead to the obstruction of OMP folding, affect the function of the outer membrane, and eventually lead to bacterial death. In view of the important role of the BAM complex in OMP biogenesis, the BAM complex has become an attractive target for the development of new antibacterial drugs against Gram-negative bacteria. Here, we summarize the structure and function of the BAM complex and review the latest research progress of antibacterial drugs targeting BAM in order to provide a new perspective for the development of antibiotics.

ATP‐independent assembly machinery of bacterial outer membranes: BAM complex structure and function set the stage for next‐generation therapeutics

“…The emergence of multi‐drug resistance in bacterial pathogens is now one of the greatest challenges to public health worldwide (Overly Cottom et al, 2023; Xu et al, 2023). While a wide array of techniques have been employed to characterize the BAM complex, a clear consensus on its function, species‐dependent diversity, regulatory elements, and auxiliary roles in the OM, is yet to emerge.…”

“…Hence, the essential nature and accessibility of the BAM complex makes it a novel and attractive target in today's scenario with widespread antibiotic resistance (Lewis, 2020; Lithgow et al, 2023; Waller et al, 2023). Both natural and synthetic inhibitors of the BAM complex (Overly Cottom et al, 2023) (Table 1 and Figure 6) have recently been tested as potential therapeutics (Di Somma et al, 2022; Ghequire et al, 2018; Hagan et al, 2015; Hart et al, 2019; Imai et al, 2019; Li et al, 2020; Luther et al, 2019; Miller et al, 2022; Overly Cottom et al, 2023; Steenhuis, van Ulsen, et al, 2021; Storek et al, 2018; Urfer et al, 2016; Xu et al, 2023). These target either (Nikaido, 2003) structural components of BamA accessible extracellularly, or (Bos et al, 2007) essential interactions between BAM complex components, such as BamA–BamD interactions (Figures 6 and 7) (Overly Cottom et al, 2023; Srinivas et al, 2010; Xu et al, 2023).…”

“…Given the resurgence of drug‐resistant Gram‐negative bacterial pathogens, the BAM complex is being actively examined as a novel therapeutic target for inhibitor design and screens of peptidotherapeutics (Di Somma et al, 2022; Diederichs et al, 2021; Doyle & Bernstein, 2022; Ghequire et al, 2018; Hagan et al, 2015; Hart et al, 2019; Imai et al, 2019; Li et al, 2020; Luther et al, 2019; Miller et al, 2022; Overly Cottom et al, 2023; Steenhuis, van Ulsen, et al, 2021; Storek et al, 2018; Tomasek & Kahne, 2021; Urfer et al, 2016; Xu et al, 2023). Most recent advances in the identification and design of inhibitors that specifically target this essential bacterial protein (Haysom et al, 2023; Miller et al, 2022; Overly Cottom et al, 2023; Seyfert et al, 2023; Steenhuis, van Ulsen, et al, 2021; Xu et al, 2023) now offer promise in successfully developing translational therapeutics for drug‐resistant bacterial pathogens. This review presents the structures of the BAM complex and its interactome, outlines known modes of BAM complex function, and describes recent successes in the identification and characterization of BAM‐specific inhibitors as next‐generation therapeutics.…”

Identification of essential genes that support fitness ofAcinetobacter baumanniiefflux pump overproducers in the presence of fluoroquinolone

“…BamD, which is important for FQR fitness in the presence of ciprofloxacin, is essential for the assembly and proper insertion of outer membrane proteins (OMPs) (34). Interestingly, we previously showed that transposon knockouts of SurA, a nonessential periplasmic chaperone with similar function to BamD, reduces GPL strain fitness in the presence of Cip (16,34).…”

Burkholderia pseudomallei Complex Subunit and Glycoconjugate Vaccines and Their Potential to Elicit Cross-Protection to Burkholderia cepacia Complex

“…They ultimately identified 109 reactive peptides, one of which was derived from BPSL2151 [ 161 ]. Protein BLAST of the BPSL2151 sequence largely implicates this Omp85 family protein as being the Burkholderia homolog of BamA [ 162 ], one of the most highly conserved proteins found in the outer membrane proteome of virtually all known Gram-negative bacteria [ 163 ]. This high conservation is due to the integral role of the BAM complex, which serves to mediate insertion of other β-barrel proteins into the outer membrane [ 163 ].…”