FDA Approved Non-antibiotic Drugs to Combat Multiple Drug Resistant Microbes

<p>AbstractResistance to multiple antibiotics has emerged in many bacterial pathogens, with life-threatening infectionsexpected to increase to 10 million cases annually worldwide by 2050. Development of new chemotherapeuticsis a high priority with several national/international programs beginning to evaluate non-antibiotic FDA-approveddrugs for infectious disease indications. We responded to this new healthcare initiative by screening 780 FDA-approved drugs against a Tier-1 select agent in our unique biosafety containment facility. This approach is costeffective as it significantly shortens the time to market by leveraging well-defined drug structures andpharmacological properties, as well as safety profiles in patients. We identified three new ?drug leads?(doxapram, a breathing stimulant; amoxapine, an anti-depressant; and trifluoperazine, an anti-psychotic) thatshowed excellent protection from pneumonic plague in mice infected with Yersinia pestis. These drugs wereefficacious when used as a treatment option administered one to three times at a much lower human equivalentdoses. Our data show that these drugs also extend protection against an urgent healthcare threat Clostridiumdifficile, the leading cause of antibiotic-associated diarrhea, and multiple drug resistant (MDR) SalmonellaTyphimurium, representing a serious public health threat. Whole transcriptome analysis of macrophages treatedwith these drugs and infected with S. Typhimurium or Y. pestis led to the identification of potential host-directedmechanisms involved in bacterial clearance. Our observations are striking since we demonstrate that thesedrugs protect against diverse pathogens via a previously unappreciated mechanism(s) that targets host functionand not bacterial growth or virulence determinants. Based on the scientific premise that these drugs modulatecentral nervous system function to achieve clinical efficacy in patients, we hypothesize that common drug-induced neuroimmune signals may promote a robust host immune response against these pathogens. Indeedwe showed that an engineered locked chemokine dimer that effectively recruits neutrophils to the infection siteprotects mice from such infections. In Aim 1, we will optimize the protective effects of ?lead drugs? and anengineered chemokine singly, in combination, or in conjunction with standard of care antibiotics in animal modelsof C. difficile and S. Typhimurium infections. In Aim 2, we will evaluate how the ?lead drugs? promote hostdefenses against bacterial infections and determine how these therapeutics impact neutrophil and macrophageresponses from onset to the resolution phase of infection. In Aim 3, we will investigate the relationship betweenefficacy of the lead drugs and neuroimmune signaling along the microbiota-gut-brain axis, whether these leadcandidates alter composition of the microbiota prior to or after C. difficile and S. Typhimurium infections, andcharacterize the effect of the microbiota composition on the pharmacokinetics and pharmacodynamics of ourlead drugs. These studies could lead to broadly active, novel therapeutics against MDR pathogens of immediateconcern allowing rapidly moving drug candidates into preclinical and clinical studies for eventual licensure.</p>