Researchers are investigating novel antibiotics that are designed to dismantle bacteria before they can even begin to develop a resistance. Combating resistant bacteria has been—and still is—a battle of one-upmanship between drug investigators and the wily pathogens. And it’s a battle that we’ve been losing.
Each year in the United States, at least 2 million people are infected with antibiotic-resistant bacteria, and at least 23,000 people die as a result, according to the Centers for Disease Control and Prevention.
“Antibiotics are a very serious public health problem for us and it’s getting worse,” said Anthony S. Fauci, MD, director, National Institute of Allergy and Infectious Diseases. “Resistant microbes outstrip new antibiotics. It’s an ongoing problem. It’s not like we can fix it, and it’s over. We have to fight continued resistance with a continual pipeline of new antibiotics and continue with the perpetual challenge.”
Toward that effort, here are some of the next-generation antibiotics that are designed to thwart resistant microbes.
The novel antibiotic teixobactin, a cyclic depsipeptide, made headlines a few years ago when researchers announced its potential as a superbug killer. News stories heralded the compound as the first in a new class of antibiotics that could eradicate resistant superbugs, such as methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis, without detectable resistance.
In recent in vivo experiments, researchers showed that teixobactin analogues were highly potent against S. aureus, MRSA, and vancomycin-resistant enterococci. In addition, when investigators instilled a topical form of teixobactin into the eyes of mice with S. aureus keratitis, the novel antibiotic killed more than 99% of the bacteria and significantly decreased corneal edema compared with control mice.
Teixobactin works by attaching itself to the outer surface of the bacterial cell and disrupting the foundations of the cell wall, leading to cell wall rupture during cell division—and destroying the bacteria. The drug isn’t yet ready for human trials but is in preclinical development.
Lefamulin, a novel pleuromutilin antibiotic, has a unique mechanism of action—it binds to an integral part of the bacterial ribosome, which inhibits peptide transfer and, thus, prevents protein synthesis.
This novel antibiotic is effective against gram-positive and other organisms associated with community-acquired bacterial pneumonia (CABP), including Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumoniae. In the United States, CABP is the leading cause of infectious death in adults, causing more deaths than either breast or prostate cancer.
Drug maker Nabriva Therapeutics is developing both oral and intravenous forms of the drug. In a recent phase 3 clinical trial in adult patients with CABP, investigators reported that a 5-day course of oral lefamulin was as effective as a 7-day course of oral moxifloxacin. Lefamulin, however, has the advantage of little or no drug resistance at present, unlike moxifloxacin. The downside to lefamulin in this trial was that significantly more patients experienced adverse effects of diarrhea and nausea than those on the fluoroquinolone.
Nabriva expects to file a New Drug Application with the US Food and Drug Administration in the fourth quarter of 2018. The company is also investigating lefamulin for use against acute bacterial skin and skin structure infections.
Gepotidacin is a novel antibiotic that’s currently in clinical trials for treating Neisseria gonorrhoeae infection (gonorrhea), including multidrug-resistant strains. In recent decades, N. gonorrhoeae has developed resistance to most antibiotics used for treatment, which suggests that gonorrhea may one day become virtually untreatable.
Gepotidacin has a novel mechanism of action for an antibiotic, which could prevent it from becoming resistant. Like several new cancer drugs, gepotidacin is a topoisomerase inhibitor—it blocks the enzyme topoisomerase from assisting in DNA replication in bacterial cells, stopping the infection in its tracks.
In a recent phase 2 clinical trial in adults with uncomplicated urogenital gonorrhea, investigators showed that oral gepotidacin was at least 95% effective against N. gonorrhoeae. “Gepotidacin may prove to be a therapeutic alternative for the treatment of uncomplicated gonorrhea,” the investigators concluded.
These are but three of the novel antibiotics currently under investigation. For a look at more antibiotics in the pipeline, visit the World Health Organization’s page on antibacterial products in clinical development for priority pathogens.