A new weapon in the arsenal as discovery offers hope in the fight against antibiotic resistance.
In the relentless war against infectious diseases, a breakthrough has emerged: a novel class of antibiotics demonstrating efficacy against multidrug-resistant (MDR) bacteria. With the alarming rise of resistance threatening the effectiveness of conventional antibiotics, the discovery of this new class offers a ray of hope in combating some of the most challenging pathogens.
Describing a new class of antibiotics developed as a part of multi-national consortia, researchers at Uppsala University published their work in the Proceedings of the National Academy of Sciences of the USA. The class of compounds they describe target a protein, LpxH, which is used in a pathway by Gram-negative bacteria to synthesise their outermost layer of protection from the environment, called lipopolysaccharide. Not all bacteria produce this layer, but those that do include the organisms that have been identified by the World Health Organization as being the most critical to develop novel treatments for, including Escherichia coli and Klebsiella pneumoniae that have already developed resistance to available antibiotics.
Traditional antibiotics struggle to penetrate the complex cell structures of Gram-negative bacteria, making them particularly challenging to treat. However, the researchers have homed in on a promising target: the lipid A biosynthesis pathway, a crucial component of the outer membrane of Gram-negative bacteria.
Inhibiting the biosynthesis of lipid A disrupts the integrity of the outer membrane, rendering bacteria vulnerable to attack. One key enzyme in this pathway, LpxH, has emerged as a prime target for the development of new antibiotics. By blocking LpxH, researchers aim to cripple the bacteria's defence mechanisms and restore the efficacy of antibiotic treatments.
The journey towards this breakthrough has been marked by challenges and setbacks. Through strategic adjustments, researchers have overcome hurdles and produced analogs with improved affinity and efficacy against MDR bacteria. While initial studies have focused on efflux-defective strains, efforts are underway to broaden the spectrum of activity to include high-priority pathogens like A. baumannii and P. aeruginosa.
In vitro and in vivo experiments have underscored the potency of these new antibiotics against a diverse array of MDR strains. Importantly, these compounds have demonstrated effectiveness in animal models of infection, offering hope for their clinical application in treating life-threatening bacterial infections.
The significance of this breakthrough extends beyond the laboratory. With antibiotic resistance posing a growing threat to public health, the discovery of a new class of antibiotics heralds a potential turning point in the fight against MDR bacteria. By targeting vulnerabilities in the bacterial cell wall, these antibiotics offer a powerful weapon against some of the most formidable pathogens.
Full study available here: https://www.pnas.org/doi/10.1073/pnas.2317274121
