A drug that destroys the outer membrane of certain bacteria could work against infections when antibiotics fail. It successfully killed a bacterial species resistant to most treatments and is currently being tested for safety in humans.
Antibiotic resistance is a major threat to global health. In 2019, it killed about 1.3 million people worldwide and contributed to almost 4 million additional deaths. Of particular concern is Carbapenem-resistant Acinetobacter baumannii (CRAB), which the World Health Organization classifies as a priority 1 critical pathogen due to a lack of effective treatments. It has an estimated mortality rate of 40 to 60 per cent.
So, and at Roche, a pharmaceutical company in Switzerland, and their colleagues measured the antibacterial activity of roughly 45,000 drug candidates belonging to a class of compounds called tethered macrocyclic peptides, which are structurally similar to antibiotics. They applied each compound to various cultured microbes and discovered one inhibited the growth of CRAB. They then modified the compound鈥檚 structure to boost its efficacy against CRAB and reduce its toxicity to other cells.
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The researchers tested the resulting drug candidate, named zosurabalpin, in six immunocompromised mice with CRAB lung infections. Two hours after infection, the mice received injections of zosurabalpin every 6 hours for 24 hours. An equal number of mice received tigecycline, one of the few antibiotics currently used for CRAB.
Afterwards, the researchers measured the number of bacteria in the animals鈥� lungs. They found that those treated with zosurabalpin had a 100,000-fold decrease in bacteria, on average, compared with those receiving tigecycline.
Further experiments revealed zosurabalpin kills CRAB by disrupting the transportation of molecules that form its outer membrane. These molecules make up the outer membranes of other antibiotic-resistant bacteria, too, says Bradley. 鈥淪o, it does open up a lot of doors in terms of thinking about new chemical compounds that can be used to inhibit that process in other pathogens,鈥� he says.
However, 鈥渨e can鈥檛 confidently say this is an effective human medicine yet. There鈥檚 a long way to go before we get there鈥�, says Lobritz. Zosurabalpin is currently in phase I clinical trials to determine its safety in humans, he says.
鈥淭he pipeline for new antibacterial agents is relatively thin. Though zosurabalpin alone will not address the antimicrobial crisis, we think that innovative solutions like this are more and more needed,鈥� says Lobritz.
Journal reference:
Nature ,
