Fiscal Year 2017 (FY17) Peer Reviewed Medical Research Program (PRMRP) Topic Area: The proposal seeks to develop a conceptually innovative intervention to treat infections caused by multidrug-resistant pathogens, a topic listed in the “Antimicrobial Resistance” section of the FY17 PRMRP Area of Encouragement.

Problem to Be Addressed in the Project: The project aims to develop a conceptually novel therapy to treat multidrug-resistant bacterial infections and manage combat-related and other drug-resistant infections. Military personnel deployed in remote locations often experience stress, inadequate healthcare, and other factors that contribute to increased susceptibility to bacterial infections. Wounds, burns, and body traumas greatly increase the risk of acquiring infections by drug-resistant pathogens extant in hospital environments that have adapted to hide among drug-susceptible bacteria and cause chronic infections. Among such bacteria are Staphylococcus aureus or golden staph and Pseudomonas aeruginosa, which have acquired resistance to many powerful antibiotics, and each of which accounts for approximately 20 percent of world-wide hospital infections. These pathogens also prevail in combat-related infections, accounting for a large portion of multidrug resistance isolates associated with combat wounds and burns.

Overview of the Proposed Research: The constant emergence of drug-resistant bacterial strains necessitates the identification of novel potent antimicrobials. We propose a conceptually novel therapeutic treatment for drug-resistant infections. Rather than developing new antibiotics, we propose to develop a universal potentiator of currently available antibiotics. In addition to their primary mechanism of action, many antibiotics inflict stress on bacterial cells that contributes to the antibiotic killing effect. Our pioneering studies have identified hydrogen sulfide as a bacterial molecule that provides protection against stress. In our proof-of-concept research, we identified chemical compounds that specifically inhibit the biosynthesis of this stress-relieving molecule in various bacteria, including S. aureus and P. aeruginosa. Although these compounds do not kill bacteria themselves, they increase bacterial susceptibility to antibiotics and potentiate bacterial killing in combination therapies with antibiotics, even if the antibiotics are administered at 10- to 100-fold lower doses than those currently recommended. Therefore, a regular or lower dose of an antibiotic in such therapy will overcome the acquired antibiotic resistance. We propose to improve our leading inhibitors of hydrogen sulfide biosynthesis and develop more effective novel and specific compounds to treat military-relevant drug-resistant infections. Within the 3-year timeline of the project, we anticipate developing therapies that combine hydrogen sulfide inhibitors and clinical antibiotics to target the hydrogen sulfide biosynthetic pathway in drug-resistant S. aureus and P. aeruginosa. Such therapies represent a conceptually innovative treatment approach that has a potential to target many bacterial species associated with combat-related and hospital infections.

Impact of the Research: Antibiotic resistance kills approximately 700,000 people each year worldwide. The Centers for Disease Control and Prevention (CDC) has reported that healthcare-associated infections affect over 700,000 Americans and contribute to nearly 75,000 deaths per year. The development of new antibacterial therapies proposed here is aimed at the most dangerous drug-resistant bacteria, including species classified by the CDC as “serious” threats, and species listed by the World Health Organization as Priority 1 (Critical) and Priority 2 (High) pathogens in 2017. Therefore, the project has ultimate applicability to all sufferers from bacterial infections and especially to military personnel and Veterans who are at high risk of contracting life-threatening combat-related infections. The principal component of our therapy, a hydrogen sulfide inhibitor, renders bacteria less resistant to bactericidal antibiotics so that the antibiotics are active at much lower concentrations. The addition of the inhibitor to the treatment regimen will restore the efficacy of the antibiotics to which bacteria have developed resistance, helping to avert the impending public health crisis, relieving the necessity to continually and rapidly develop new classes of antibiotics, and allowing the reduced use of new antibiotics. Therefore, in the long term, our combination therapy will delay the emergence of new drug resistance and facilitate the responsible stewardship of antimicrobial therapeutics. Furthermore, in the short term, our therapy will create new options to treat bacterial infections with “normal” antibiotic sensitivity by shortening the duration of treatment, reducing side effects caused by high antibiotic doses, decreasing cases of recurrent infection, and enabling therapy in the contexts where current drugs lack sufficient bactericidal efficacy.