Carbapenemase-Stable Carbapenem Antibiotics for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections

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Acinetobacter baumannii is listed by the CDC as a clinical pathogen that poses a serious antibiotic resistance threat in the United States, due to its resistance to the last resort carbapenem antibiotics (carbapenem-resistant A. baumannii or CRAb), which were the drugs of choice for treatment of infections caused by this microorganism. In addition, CRAb is often resistant to antimicrobial agents of different classes (multi-drug-resistant A. baumannii or MDRAb), which severely limits available therapeutic options. The major mechanism of resistance of A. baumannii to carbapenems is production of antibiotic-inactivating enzymes, carbapenem-hydrolyzing class D β- lactamases or CHDLs. In addition, carbapenemases of classes A and B, sensitivity of carbapenem targets (bacterial penicillin-binding proteins or PBPs), rates of antibiotic penetration into the bacterial cell and their expulsion by efflux pumps can also contribute to resistance. Levels of resistance to carbapenems reach up to 90% in some parts of the world, and mortality rates from infections caused by such bacteria are staggeringly high, up to 50%. Our long-term goal is to develop novel antibiotics for treatment of deadly MDRAb infections. Over the last decade, the Vakulenko group has performed in-depth characterization of clinically important CHDLs, which provides guidance for development of a new generation of carbapenems capable of inhibiting these enzymes. Concurrently, Dr. John Buynak’s (co-PI) group developed dozens of novel atypically-modified carbapenem antibiotics. We evaluated these antibiotics for their activity against MDRAb and demonstrated that three of them possess superior activity (when compared to commercial carbapenems) against MDRAb. All three inhibited the most prevalent A. baumannii CHDL, OXA-23, and had varying spectra of inhibitory activity against other CHDLs and carbapenemases of other classes. One of these compounds had an unprecedented wide spectrum of activity and resisted hydrolysis by a wide range of clinically important carbapenemases of all molecular classes. In this grant application, we propose to perform detailed characterization of our novel carbapenem antibiotics. We will determine activity of our compounds against A. baumannii strains expressing major CHDLs and other carbapenemases and unveil kinetic and structural features responsible for their ability to inhibit these enzymes (Aim 1). We will study interaction of our novel carbapenems with their targets, PBPs, and determine to what extent efflux pumps and porins influence bacterial resistance to these antibiotics (Aim 2). We will design and characterize several dozen novel carbapenem antibiotics to further improve their antimicrobial activity by enhancing their inhibitory potency against various carbapenemases, improving affinity for PBPs and increasing penetration rates and resistance to efflux (Aim 3). We will perform in vitro characterization of our best novel carbapenems to assess their solubility, stability and toxicity. Finally, our best compounds will be evaluated in animal studies to appreciate their potential as novel therapeutic agents against MDRAb (Aim 4).