Cystic Fibrosis patients are highly susceptible to infections with Mycobacterium abscessus. This pathogen is detected in the sputum of ~13% of cystic fibrosis patients in the US. Mycobacterium abscessus strains that are resistant to meropenem and imipenem, two powerful carbapenem drugs that are currently in clinical use, are routinely seen in US hospitals. Treatment and control of infections that are resistant to existing drugs requires new antibiotics that inhibit enzymes that have not been targeted.
The aim of this proposal is to develop a more potent regimen based on new carbapanem drugs that are not currently used for treatment of Mycobacterium abscessus. We recently discovered a novel enzyme, namely LD-transpeptidase, in Mycobacterium tuberculosis that is required for growth, survival and virulence of this pathogen (Gupta et al, Nature Medicine, 2010; Erdemli et al, Structure, 2012; Schoonmaker, Journal of Bacteriology, 2014). This enzyme is also present in Mycobacterium abscessus (Lavollay et al, Journal of Bacteriology, 2011). While we have already reported that this novel enzyme activity is inhibited by meropenem and imipenem (Erdemli et al, Structure, 2012), recently we confirmed that newer carbapenems that are not yet in clinical use are much more potent and inhibit growth of not only Mycobacterium tuberculosis but also Mycobacterium abscessus. Therefore, this proposal aims to translate recent basic findings of a newly discovered enzyme to develop novel regimens based on new carbapenems for treatment of Mycobacterium abscessus infections that are resistant to currently available drugs. Our proposal is timely and addresses the need for new drugs with high potency and specificity to treat Mycobacterium abscessus infections in cystic fibrosis patients.
A significant proportion of cystic fibrosis patients are morbid with chronic Mycobacterium abscessus infection. The number of drug resistant Mycobacterium abscessus strains isolated from cystic fibrosis patients around the country is steadily increasing making it increasingly difficult to manage these infections. Therefore, new drugs and novel regimens are acutely needed to effectively treat these infections and this proposal is directly aimed at developing a novel regimen using carbapenems, a class of powerful antibiotics never used for treating Mycobacterium abscessus infection, by inhibiting a novel class of enzyme present in this pathogen.