Researchers in California have developed a new antibiotic that could turn the tide in the urgent battle against multi-drug-resistant bacteria.
The novel agent, known for now as G0775, showed striking efficacy at eliminating more than a dozen strains of the most dangerous antibiotic-resistant gram-negative bacteria – so-called ‘superbugs’ – both in a dish and in infected mice. Moreover, the drug’s mechanism of action appears to avoid the existing routes by which bacteria can evolve resistance. The results were published this week in Nature.
Most of the bacteria that concern us humans fall into one of two categories: gram-negative or gram-positive. These terms describe the type of outer surface that a bacterium sports in terms of whether or not a particular dye will stain it purple. Gram-positive species hold the stain thanks to their thick protein and sugar-based shell, which surrounds a single membrane. Gram-negative bacteria have a thin shell that is sandwiched by two membranes, and thus the dye does not cling on. It has, historically, been easier to create drugs against gram-positive varieties – such as Staphylococcus and Streptococcus – because targeting the outer shell allows us to kill bacteria without harming our own cells, which don’t have this structure.
Gram-negative bacteria present a much greater challenge for drug developers, so much so that it has been 50 years since a new agent has been approved, according to Christopher Heise and Peter Smith of Genentech, two of the researchers on the G0775 development team. In an interview with Research Gate, the duo explained that the dual membranes “effectively [function] as a molecular sieve to preclude penetration of antibiotics into the bacterial cell.”
Coincidentally, gram-negative bacteria’s drug-evading membranes are also central to why we so sorely need more treatments against them. The extreme and sometimes fatal toxicity of gram-negative infections – like those of Escherichia coli, Neisseria gonorrhoeae, Yersinia pestis (the plague), and Vibrio cholerae (cholera), to name a few – is caused by an immune response to a membrane component called lipid A.
“The situation is particularly worrisome for a group of gram-negative bacteria found predominantly in hospitals. Without an entirely new way to combat them, gram-negative bacteria pose a serious threat to a highly vulnerable population,” the pair added.
Their journey to develop G0775 began with several years’ worth of investigations into arylomycins, a class of recently discovered, naturally occurring substances that have weak activity against a handful of gram-negative species. Heise and Smith’s team were drawn to these molecules because previous work had revealed that arylomycins interfere with gram-negative bacteria’s ability to transport crucial proteins across their membranes by blocking an enzyme called bacterial type I signal peptidase (SPase).
Once they had characterized the molecules’ SPase-inhibiting pathway, the scientists could start trying to construct derivatives with higher potency and the ability to kill multiple species of bacteria.
After selecting G0775 as their most promising candidate, the team tested it against a panel of the deadliest gram-negative bacteria found in US hospitals. One of these strains is currently resistant to 13 different antibiotic classes.
While it is easy to get excited and proclaim that the long-awaited promise of new antibiotics has now arrived, the authors emphasize that it will be some time before G0775 is tested in people. Plus, we still know nothing about the drug’s safety and potential side effects.
And finally, it is likely only a matter of time before bacteria find a way to resist any new agents we throw at them – evolution is referred to as a perpetual arms race, after all.