Structure-guided design of apramycin analogs to avoid resistance and enhance efficacy

The National Institute of Allergy and Infectious Diseases awarded Beth Israel Deaconess Medical Center, Inc. $844,925 on August 17, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to design apramycin analogs targeting resistance in gram-negative pathogens.

The project focuses on structure-guided derivatization of apramycin to block inactivation by aminoglycoside-modifying enzymes and extend activity spectrum to multidrug-resistant gram-negative ESKAPE pathogens—carbapenem-resistant Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa—while optimizing ribosomal selectivity and minimizing toxicity. Apramycin retains activity against strains expressing ribosomal methylases that render clinically approved aminoglycosides ineffective and avoids the nephrotoxic and ototoxic side effects that have limited use of other aminoglycosides. The work proposes combinatorial modifications to apramycin's 4-aminoglucose and 2-deoxystreptamine rings to develop highly selective, potent analogs with broad in vitro and in vivo activity.

Performance occurs in Boston, Massachusetts. The period of performance runs through July 31, 2031. The assistance type is a Project Grant, supporting investigator-initiated research at a nonprofit academic medical center.

Abstract

New antimicrobials are urgently needed to address the emergence of drug resistance in gram-negative pathogens. Apramycin is an unusual, glycosylated aminocyclitol that has broad-spectrum activity against carbapenem-resistant enterobacterales (CRE), acinetobacter baumannii, and pseudomonas aeruginosa. These pathogens are currently often untreatable or treatable only with toxic antimicrobials. Therefore, the CDC now categorizes such organisms in their top antibiotic resistance threat level. In contrast to clinically approved aminoglycosides including plazomicin, the apramycin scaffold retains activity against strains expressing widely circulating ribosomal methylases that are found at high frequency in NDM-1 carbapenemase-producing strains. Importantly, apramycin itself does not appear to have significant nephrotoxic and ototoxic side effects that have limited clinical use of other aminoglycosides. Indeed, there is only a single circulating aminoglycoside modifying enzyme (AME) in gram-negatives, present in ~30% of CRE strains, (extremely rare to absent in a. Baumannii and p. Aeruginosa), that inactivates APR through acetylation at the c-3 amine position in the 2-deoxystreptamine (2-DOS) ring. Mics in a. Baumannii and p. Aeruginosa are relatively elevated based on action of identified RND efflux pumps. Based on the underlying compelling properties of apramycin, we propose to address the hypothesis that combinatorial derivatization of apramycin's 4-aminoglucose and 2-DOS rings can block inactivation by AME, thereby extending activity spectrum broadly to multidrug-resistant gram-negative eskape pathogens, while optimizing discriminatory interactions with the bacterial ribosome. Together, our goal will be to develop highly selective, potent, non-toxic apramycin analogs with broad in vitro activity spectrum and compelling in vivo activity.