NIH Funds Search for Alternatives to Traditional Antibiotics

Agency sets sights on growing resistance threat

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has awarded approximately $5 million in funding for 24 research projects seeking to develop nontraditional therapeutics for bacterial infections to help address the growing health threat of antibiotic resistance.

“The discovery, development, and deployment of antibiotics have transformed medicine; however, microbes continually evolve and become resistant to these lifesaving drugs,” said NIAID director Anthony S. Fauci, MD. “New strategies are desperately needed to treat patients with antibiotic-resistant infections that often are deadly. These new NIAID grants will provide funding to researchers developing unique, nontraditional therapies that could complement or even replace currently available antibiotics that are losing effectiveness.”

Increasing resistance to antibiotics coupled with the slow pace of new antibiotic development threatens to erode the past 70 years of progress in fighting life-threatening bacterial infections, the NIAID says. The overuse and abuse of antibiotics drives this issue and, as a consequence, bacteria adapt to antibiotics designed to destroy them, making the drugs less effective and allowing antibiotic-resistant strains to survive and multiply.

A nontraditional therapeutic is an antibacterial treatment that works differently than traditional antibiotics, which typically target one or more essential pathways, such as those involved in cell-wall and protein synthesis, to directly kill or inhibit the growth of many types of bacteria.

One nontraditional approach, called therapeutic bacteria, uses harmless bacteria found in or added to the human microbiome to target or control the growth of harmful ones. Another alternative approach is bacteriophage or “phage” therapy, which uses viruses that affect only bacteria to reduce or eliminate those bacteria in humans. Other examples of nontraditional approaches include adding decoy targets to prevent bacterial pathogens from producing disease, enhancing human immune responses to pathogens, and developing drugs that incapacitate the pathogen’s ability to adapt and compete.

During the past decade, the NIAID has supported numerous research initiatives to advance promising therapeutic products against high-priority pathogens. Therapeutic development projects currently supported by the agency include the creation of six synthetic tetracyclines that can treat different types of bacterial infections and that are not subject to typical tetracycline resistance mechanisms, and therapeutics containing gallium citrate, a metal with well-documented antibacterial properties.

In addition, combination therapies that target both essential functions and resistance factors hold promise for treating tenacious gram-negative infections. For instance, the NIAID is supporting the preclinical development of beta-lactamase inhibitors and efflux pump inhibitors that can be paired with previously approved antibiotics to treat resistant infections. Numerous other combination-therapy approaches are also being explored, including immunomodulators, biofilm disruptors, and signaling inhibitors.

Another therapeutic approach repurposes old drugs by using new technologies to optimize dosing levels and the duration and route of administration, and to identify promising combination drug therapies based on current pharmacokinetic and pharmacodynamic principles. Colistin, an antibiotic approved in the late 1950s that fell out of widespread use in the 1970s because of toxicity issues, is one such drug. NIAID-supported researchers discovered that delivering a higher initial or loading dose of colistin enhances its effectiveness and reduces its toxic side effects.

Sources: NIH; January 12, 2016; and NIAID; 2014.