RESUMO
The global increase in multi-drug-resistant bacteria is severely impacting our ability to effectively treat common infections. For Gram-negative bacteria, their intrinsic and acquired resistance mechanisms are heightened by their unique cell wall structure. The cell wall, while being a target of some antibiotics, represents a barrier due to the inability of most antibacterial compounds to traverse and reach their intended target. This means that its composition and resulting mechanisms of resistance must be considered when developing new therapies. Here, we discuss potential antibiotic targets within the most well-characterised resistance mechanisms associated with the cell wall in Gram-negative bacteria, including the outer membrane structure, porins and efflux pumps. We also provide a timely update on the current progress of inhibitor development in these areas. Such compounds could represent new avenues for drug discovery as well as adjuvant therapy to help us overcome antibiotic resistance.
RESUMO
The rise of antibiotic resistance combined with the lack of new products entering the market has led to bacterial infections becoming one of the biggest threats to global health. Therefore, there is an urgent need to identify novel antibiotic targets, such as dihydrodipicolinate synthase (DHDPS), an enzyme involved in the production of essential metabolites in cell wall and protein synthesis. Here, we utilised a 7-residue sequence motif to identify mis-annotation of multiple DHDPS genes in the high-priority Gram-negative bacteria Acinetobacter baumannii and Klebsiella pneumoniae. We subsequently confirmed these mis-annotations using a combination of enzyme kinetics and X-ray crystallography. Thus, this study highlights the need to ensure genes encoding promising drug targets, like DHDPS, are annotated correctly, especially for clinically important pathogens. PDB ID: 6UE0.
