Antibiotics are one of our main weapons against infections. The problem is that many bacteria are becoming resistant to most of the antibiotics we use to treat them, and those 'superbugs' have created an urgent threat to our global health. A research group found a new way to hit a well known bacterial target and have developed a drug to hit it.
The new class of antibiotics hits an enzyme called LpxC that's critical to forming the outer membrane of some types of bacteria. An international team of scientists showed that a LpxC inhibitor could treat Yersinia pestis, the bacteria that causes plague, as well as several multi-drug resistant and extremely drug-resistant strains of bacteria.
Biochemist and structural biologist Pei Zhou at Duke University and biologist Florent Sebbane from the French National Institute of Health and Medical Research led the study. Chemist Eric Toone from Duke University joined them in the development of the drug. The study was published July 25 in the journal mBio.
Scientists have developed antibiotics that work on different parts of the bacteria or affect its processes. The way that antibiotics' work usually falls into a few categories: they can interfere with the cell wall, protein or DNA synthesis; or they can affect leakiness of the cell membrane leading to the death of the microbe.
The new antibiotic targets an essential enzyme in the biosynthesis of the lipid A (fat) component of the outer membrane of Gram-negative bacteria, like E. coli. Even though LpxC was first suggested as a target for antibiotics decades ago, researchers couldn't find an inhibitor of LpxC that was safe to use at effective levels.
Zhou had already found a LpxC inhibitor called LPC-058 that showed good antibacterial activity, but when it was tested it in mice, there were serious side effects of diarrhea, white blood cell accumulation in their lungs and intestines, and liver toxicity at the highest dose.
The new research describes another LpxC inhibitor, LPC-069, that is an effective killer of drug-resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii and dozens of species of bacteria isolated from hundreds of samples from hospitalized patients.
To test the effectiveness of LPC-069 against Yersinia pestis, the gram-negative bacteria that causes bubonic plague, the scientists tested the compound in mice. They injected 15 mice with Yersinia pestis and left some mice untreated. Eighteen hours after infection, the researcher dosed mice with LPC-069. Five days after that, none of the untreated mice had survived, but all mice treated with LPC-069 were still alive. Autopsies done on the mice showed that the LPC-069 had successfully cured the plague, ridding the mice of the bacteria.
The new class of antibiotics may yield drugs that can help fight both the urgent threat of antibiotic resistant bacteria and the growing threat of life-threatening gram-negative bacterial infections.