A potential antibiotic against drug resistant Mycobacteroides abscessus

In patients with structural lung diseases, such as bronchiectasis or cystic fibrosis, infections with non-tuberculous mycobacteria are often viewed as the most difficult invasive pulmonary infections to treat. Of these organisms, the rapidly growing Mycobacteroides abscessus is considered to be the most virulent, with inherent and growing spontaneous resistance to available antibiotics. Despite prolonged treatment, sputum culture conversion rates as low as 25% and cure rates of 30–50% in patients with pulmonary M.abscessus infection underscore the need for new antibiotics with improved activity. Previous study findings suggest that among all β-lactam subclasses, faropenem is the most potent and selective inhibitor of L,D-transpeptidases of several bacteria, including M. tuberculosis and M. abscessus. Based on these findings researchers reassessed the potential of the penem subclass to develop new therapeutics against these bacteria.

Before the compound, called T405, can move closer to becoming a clinical treatment, researchers need to improve its pharmacological potency using a preclinical animal model of the infection.

Researchers identified an initial antimicrobial activity of T405 from a screen of a library of penems synthesized in-house that built upon the penem core while varying the sidechains branching from C2 of the carbon-carbon double bond. They found that the minimum inhibitory concentration (MIC) of T405 against Mycobacterium tuberculosis reference strain H37Rv of 0.5–1 µg/mL which is similar to that of meropenem, the carbapenem currently recommended for treating select drug-resistant tuberculosis. Further, they determined the MIC of T405 against M. abscessus reference strain ATCC 19977 and found it to be 2 μg/mL.

They reported the MIC50 and MIC90 of T405 are significantly lower compared to that of imipenem and cefoxitin, two β-lactams that are currently recommended as first-line treatment for M. abscessus infections. T405 activity against diverse clinical isolates indicated that it may be effective against resistant M. abscessus strains.

When tested in combination with the β-lactamase inhibitor avibactam, the researchers found T405 also demonstrated an ability to prevent the bacteria from developing resistance. 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.

Pharmacokinetic profile of T405 in mice showed the absence of toxicity at elevated dosage, which supports the clinical potential of this compound. T405 was also well tolerated in mice and could be administered less than current treatments, exposing patients to fewer toxic side effects such as deafness.

The authors concluded, "Our study demonstrates that there is yet untapped potential for the further development of β-lactams. The new penem reported here exemplifies such an agent with promise for further pre-clinical development to treat drug-resistant M. abscessus disease".

For further information:

https://www.nature.com/articles/s42003-020-01475-2#Sec6