Scientists at St. Jude Children’s Research Hospital are tackling Mycobacterium abscessus (Mab) antibiotic resistance. This naturally antibiotic-resistant pathogen is becoming more prevalent, highlighting the urgent need for novel therapeutics. To address this, the scientists designed new versions of the drug spectinomycin that overcome efflux, the main mechanism driving resistance. The work was published today in Proceedings of the National Academy of Science.
Mab infections are increasingly found 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.
“We chemists are in a race against the pathogens. We make stronger antibiotics, and the pathogens become more resistant,” said corresponding author Richard Lee, PhD, St. Jude Department of Chemical Biology and Therapeutics.
Scientists at St. Jude 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.
“By re-engineering the molecule through structure-based drug design, we and our collaborators have adapted the antibiotic to increase its activity,” Lee added.
Overcoming efflux to make a more effective antibiotic
Through their work, the scientists unraveled the mechanism of action by which eAmSPCs are more effective: they circumvent efflux. Efflux is the process that cells use to get rid of a drug — imagine pumping water out of a flooded basement— and is a significant mechanism by which cells become resistant to therapy.
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.
“Over the past two decades, we’ve seen a massive increase in the number of infections caused by non-tuberculous mycobacteria like Mab,” said co-first author Gregory Phelps, PharmD, St. Jude Graduate School of Biomedical Sciences. “We had a place to start with this naturally occurring antibiotic, which, through modification, we’ve made much more efficacious against this clinically relevant pathogen.”
The researchers also found that eAmSPCs work well with various classes of antibiotics used to treat Mab and retain their activity against other mycobacterial strains. Collectively, this work demonstrates that eAmSPCs should be further studied and developed because once issues of tolerability and safety are addressed, these compounds could become next-generation therapeutics.
“It is challenging to attract pharmaceutical companies to develop new antibiotics for several economic reasons,” said Phelps. “If we can boost the drug pipeline against this 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.”
Authors and funding
The study’s co-first author is Martin Cheramie of St. Jude. Other authors include Petra Selchow and Dal Molin, University of Zurich; Michael Meuli, Erik Bottger, and Peter Sander, University of Zurich and National Reference Center for Mycobacteria (Switzerland); Benjamin Killam, Zaid Temrikar, Pradeep Lukka, Bernd Meibohm, and Yury Polikanov, University of Illinois at Chicago; and Dinesh Fernando, Christopher Meyer, Samanthi Waidyarachchi, Suresh Dharuman, Jiuyu Liu, Patricia Murphy, Stephanie Reeve, Laura Wilt, Shelby Anderson, Lei Yang, and Robin Lee, St. Jude.
The study was supported by the National Institutes of Health (R01-AI157312, F31-AI169961, P30-CA021765, R01-GM132302), the Illinois State startup funds, the Swiss National Science Foundation (310030_197699), Swiss Federal Office of Public Health (3632001500), Swiss Joint Program Initiative Antimicrobial Resistance (JPIAMR-ACOMa-2002-050), the University of Zurich, and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.