In previous blogs we have discussed the global threat of antimicrobial resistance and some of the approaches that have been taken to develop new antibiotics in response to this threat. In particular, antimicrobial resistance of gram-negative bacteria is a major concern and no new classes of antibiotics that are effective against this type of bacteria have been discovered since the 1960s. However, recent studies describe several compounds that leverage a novel approach to target gram-negative bacteria. These results have sparked optimism that a new wave of antibiotics is around the corner.
A particular challenge that has hindered the development of drugs against gram-negative bacteria is the presence of a tough outer membrane surrounding these microbes, which provides a robust barrier against the entry of small-molecule antibiotics. In parallel, efflux pumps transport antibiotics that do enter back out of the bacterial cell. Together, these defence mechanisms have greatly contributed to the rising antimicrobial resistance of gram-negative bacteria by hindering successful entry of drug molecules.
Instead of relying on penetration of the outer membrane, the new approaches target proteins that are exposed on the surface of bacterial cells. These outer membrane proteins are important for the survival of bacteria and play a key role in processes including membrane biogenesis and transportation. Murepavadin is the first-in-class outer membrane protein-targeting antibiotic. This drug binds to LptD, an essential surface protein in gram-negative bacteria and disrupts biogenesis of the outer membrane, leading to bacterial cell death. The antibiotic activity of Murepavadin is specific to Pseudomonas bacteria and the drug has shown potential in treating chronic lung infections, including those associated with cystic fibrosis, where the rising antibiotic resistance of Pseudomonas is a major challenge. Murepavadin holds promise in treating infections where other drugs may fail, but remains in the early stages of drug development. An inhalation-based form of Murepavadin is currently in preclinical trials, and progression to clinical trials is expected shortly.
In a continuation of this pioneering work, a team from Switzerland has recently developed synthetic antibiotics by linking Murepavadin with another bactericidal compound known to bind to the surface of gram-negative bacteria. Unlike the pathogen-specific activity of Murepavadin, the resultant chimeric compounds possess broad-spectrum antimicrobial activity against a range of gram-negative bacteria. Interestingly, the lead compounds from this study have a different target to Murepavadin. Rather than LptD, strong interactions were found with another surface protein, BamA.
BamA is another ubiquitous gram-negative bacteria surface protein which a growing body of work has identified as a novel target. Earlier research carried out by Genentech showed that the binding of an antibody to BamA leads to the inhibition of bacterial cell growth. Although the antibody was not suitable for use as a therapeutic due to limited cell surface accessibility, another recent study has identified a natural antibiotic that also utilises BamA to target gram-negative bacteria. Produced by bacteria that live in the gut of nematode worms for protection against other invading microorganisms, Darobactin is another lead compound in this new class of potential antibiotics. Mechanistic studies show that this natural antibiotic acts by inhibiting BamA function, further demonstrating the potential of BamA as an effective target for future antibiotic development. Together, these studies indicate that interference of the outer membrane is a promising new strategy in the ongoing fight against gram-negative bacteria.
The rise of antimicrobial resistance has created an urgent need for the development of new antibiotics. Whilst further testing is required before these compounds can be approved for therapeutic use, outer membrane proteins are proving to be promising targets for the first set of new antibiotics in recent decades, offering hope in the ongoing battle against antimicrobial resistance.
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