A breakthrough in battling resistance with next-generation antibiotics

Mycobacterium abscessus (Mab) infections are becoming increasingly common in health care settings. Such infections can be hazardous for patients with compromised lung function, such as in cystic fibrosis, or who are immunologically compromised, such as in childhood cancer. These infections are treated with long courses of antibiotics and can result in poor outcomes. The emergence of Mab and other similar pathogens presents a growing and deeply concerning public health threat because there are few effective therapeutic options and a limited drug development pipeline. 

When treating Mab, clinicians have a limited number of effective antimicrobials from which to choose. However, resistance has emerged to these drugs, limiting the available treatment options and leaving very few viable alternatives. Furthermore, this naturally antibiotic-resistant pathogen is becoming more prevalent, highlighting the urgent need for novel therapeutics.

“We chemists are in a race against the pathogens. We make stronger antibiotics, and the pathogens become more resistant,” said Richard Lee, PhD, Department of Chemical Biology and Therapeutics. 

Scientists at St. Jude are tackling Mab antibiotic resistance, designing new versions of the drug spectinomycin that overcome resistance mechanisms. In the study, published in Proceedings of the National Academy of Science, the researchers modified the naturally occurring antibiotic spectinomycin to create analogs, comparable but structurally distinct N-ethylene linked aminomethyl spectinomycins (eAmSPCs). These synthetically created eAmSPCs are up to 64 times more potent against Mab than standard spectinomycin.  

The scientists unraveled the mechanism of action by which eAmSPCs are more effective: they circumvent efflux. Efflux is the process that cells use to eliminate a drug — imagine pumping water out of a flooded basement— and is a significant mechanism by which cells become resistant to therapy. Cells use specific drug efflux pumps to expel drugs. 

The N-ethylene linkage structure of the eAmSPCs plays a critical role in how the compounds avoid efflux, suggesting that longer linkages modify how the compound is pumped out of the cell. This ultimately shifts the balance toward higher concentrations of eAmSPC within the cell and thus enhances antimicrobial efficacy.   

“By re-engineering the molecule through structure-based drug design, we and our collaborators have adapted the antibiotic to increase its activity,” Lee added. 

The researchers also found that eAmSPCs work well with various antibiotic classes used to treat Mab and retain their activity against other mycobacterial strains. Collectively, this work demonstrates that eAmSPCs should be further studied and developed. Once issues of tolerability and safety are addressed, these compounds could become next-generation therapeutics.  

“Over the past two decades, we’ve seen a massive increase in infections caused by nontuberculous mycobacteria like Mab,” said co-first author Gregory Phelps, PharmD, Graduate School of Biomedical Sciences. “If we can boost the drug pipeline against these hard-to-treat bacteria, we can potentially make a difference for patients like the ones we have here at St. Jude who are increasingly faced with limited or no therapeutic options.”