To defeat the so-called superbugs, an entirely new class of antibiotic is needed but for more than 50 years, no new effective antibiotics have been developed. Now, scientists may have finally cracked the case. A study published on 12 September in Nature has revealed a new compound that can break through the double cell wall and thick outer membrane of antibiotic-resistant bacteria. According to the authors, this “could translate into new therapies to address the growing threat of multidrug-resistant gram-negative infections” and potentially save lives.
The new promising candidate was developed through the chemical optimization of arylomycins ― a recently discovered class of natural-product antibiotics that bind and inhibit signal peptidase ― to create a molecule named G0775 that is at least 500 times more potent than naturally occurring arylomycins and exhibits potent, broad-spectrum activity against highly antibiotic-resistant gram-negative pathogens. So far, the new compound has only been tested in the lab and in mice.
Overuse and misuse of antibiotics in medicine and agriculture have led to widespread antibiotic resistance. The team, led by evolutionary biologist Peter Smith of Genentech, a biotech company in San Francisco, California, is particularly interested in the so-called ‘ESKAPE’ pathogens, including Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. These deadly bacteria strains pose the biggest threat of developing multidrug-resistant (MDR) infections and are the leading causes of hospital-acquired infections.
The ESKAPE pathogens hide inside immune cells and use them to rapidly spread throughout the body. Researchers at Genentech have already designed a new delivery system currently being tested in the clinic ― an antibody-antibiotic conjugate that finds where elusive bacteria are hiding and pounces on them. The method works well for gram-positive bacteria like the deadly Staphylococcus aureus (MRSA), however, gram-negative strains, such as Escherichia coli, K. pneumoniae, P. aeruginosa, and A. baumannii, are particularly dangerous owing to their dual membrane, so even if antibiotics can find the bacteria, they are usually unable to breach their near-impenetrable walls. At present, effective antibiotics do not exist since many gram-negative strains have developed resistance to the small number of antibiotics that actually can penetrate their outer membrane.
Arylomycins are a class of molecules that target signal peptidase, a protein located just beneath the outer membrane of gram-negative bacteria. Signal peptidase is crucial for bacteria to survive and therefore an obvious antibiotic target. Only a small group of gram-positive bacteria respond to arylomycins but they are not effective against gram-negative bacteria and no activity has been shown against the ESKAPE pathogens. Therefore, the team of researchers at Genentec set to work modifying the chemical structure of arylomycins to generate over a thousand candidate molecules. After five years, they finally found a molecule that can bind and inhibit signal peptidase in a completely novel way, thus overcoming arylomycin-resistance. The scientists were able to show the new molecule is effective even in bacteria that have developed resistance to nearly all other classes of antibiotics.
Hospital-borne infections can rapidly spread to local and global communities, thus the continuous development of novel antibiotics is critical in the fight against the constantly evolving deadliest forms of superbugs. The biggest challenge now will be getting this novel antibiotic into the clinic.
(1) Smith, P. A. et al. Optimized arylomycins are a new class of Gram-negative antibiotics. Nature (2018). DOI: 10.1038/s41586-018-0483-6