Potential Antibiotic Appears to Effectively Treat M. abscessus Infections

A newly developed antibiotic, called T405, appears to effectively kill Mycobacteroides abscessus, a difficult-to-treat bacteria that can cause serious infections in people with lung conditions like cystic fibrosis (CF).

The antibiotic was described in the study “Development of a penem antibiotic against Mycobacteroides abscessus,” published in Communications Biology.

Non-tuberculous mycobacteria (NMT) are a group of bacteria that, as the name suggests, are in the same family as the bacteria that causes tuberculosis. These bacteria are known causes of severe lung infections in people with CF, bronchiectasis, and other lung diseases.

M. abscessus is a type of NMT that is especially difficult to treat — the bacteria is resistant to many common antibiotics, including penicillin. Currently, there are no approved treatments for M. abscessus infection in the U.S.  Guidelines recommend at least a year of multi-drug therapy for such infections, and cure rates even then are between 30% and 50%.

“There are now more NTM than tuberculosis cases in the United States,” Gyanu Lamichhane, PhD, a professor at Johns Hopkins University and study co-author, said in a press release. “And this [M. abscessus] is the most virulent of all of them.”

“M. abscessus has been labeled ‘a new antibiotic nightmare’ and ‘environmental bacterium turned clinical nightmare,'” the scientists wrote in their study.

Hopkins researchers began by screening synthetic beta-lactam compounds. Beta-lactams are a class of antibiotics, the same broad category to which penicillin belongs. They work by inhibiting the production of certain components of the bacterial cell wall, which is fatal for bacteria.

The various compounds tested were, in some key respects, structurally identical, so that they could have the intended biological effect on the bacteria. However, other elements of the molecule had been modified so that, essentially, they might be more effective against the bacteria.

In these screens, T405 was identified as the most effective potential antibiotic.

Further tests evaluated how this antibiotic affected 20 strains of M. abscessus isolated from CF patients. T405 was found to be more effective than two established antibiotics (imipenem and faropenem); it was able to kill more bacteria at lower concentrations.

One common way that bacteria develop resistance to beta-lactam antibiotics is through producing enzymes that destroy the antibiotics, which are called beta-lactamases. Avibactam is a beta-lactamase inhibitor.

Co-treatment with T405 and avibactam led to increases in T405’s potency against some, but not all, of the M. abscessus strains tested. The numeric differences, however, were relatively small.

“In contrast to many commercially available [beta]-lactams  … the potency of T405 does not appear to be greatly affected by [beta-lactamase],” the researchers wrote.

Additional experiments showed a fairly low rate of spontaneous resistance against T405 in a laboratory strain of M. abscessus. When these bacteria were treated with both T405 and avibactam, the rate of spontaneous resistance decreased substantially.

The researchers suggested that this could be because avibactam increased the effective concentration of T405 — thereby allowing less of the antibiotic to kill more of the bacteria than it ordinarily would. But further research is needed to confirm this, they noted.

“If this finding is supported by further studies testing T405 with lower, more clinically relevant concentrations of avibactam or another [beta]-lactamase inhibitor, it may indicate that such a combination could reduce the risk of selection of T405-resistant mutants,” the researchers wrote.

In additional experiments using mice, the team assessed the pharmacokinetic profile of T405 (how the medication moves through and is processed by the body). Results indicated that T405 stayed in the mice’s body for a longer time than other antibiotics, indicating it may be suitable for less frequent dosing regimes.

“Our study demonstrates that there is yet untapped potential for the further development of [beta]-lactams,” the researchers concluded. “The new penem [a type of synthetic beta-lactam] reported here exemplifies such an agent with promise for further pre-clinical development to treat drug-resistant M. abscessus disease.”