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Apramycin scaffold exploration using novel glycochemistry and SAR studies to enhance activity against Acinetobacter baumannii and other multidrug-resistant Gram-negative pathogens.
George O'Doherty
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Evaluation of apramycin activity against methicillin-resistant, methicillin-sensitive, and vancomycin-intermediate Staphylococcus aureus clinical isolates. Now online, congrats to Kat Truelson, see previous post.
Kat had a very productive undergraduate experience in the laboratory while attending Boston University as an undergraduate. Her first author manuscript titled: "Evaluation of Apramycin Activity Against Methicillin-Resistant, Methicillin-Sensitive, and Vancomycin-Intermediate Staphylococcus aureus Clinical Isolates" was just accepted into Diagnostic Microbiology and Infectious Diseases, more commonly referred to as DMID. Congratulations! She found that apramycin was equally active against MSSA, MRSA, and VISA strains, and demonstrated rapid time-kill kinetics. This manuscript expands apramycin's known activity spectrum to include contemporaneous human clinical strains of multidrug-resistant carbapenem=resistant Enterobacteriaceae = CRE; Acinetobacter baumannii, and Pseudomonas aeruginosa, and now Staphylococcus aureus.
We are very excited for Kat as she is moving this summer to the University of Chicago to work on a much beloved organism, Legionella pneumophila, in Howard Shuman's laboratory. Congratulations to lab members, Anthony Kang, and colleagues for our manuscript newly accepted in Antimicrobial Agents and Chemotherapy titled: "Efficacy of Apramycin against Multidrug-Resistant Acinetobacter baumannii in the Murine Neutropenic Thigh Model"
The manuscripts describes potent in vitro and in vivo activity of the apramycin, an aminocyclitol aminoglycoside, against multidrug-resistant and extensively-drug resistant Acinetobacter baumannii. In prior manuscripts, we demonstrated broad activity against several types of multidrug-resistant pathogens including carbapenem-resistant Enterobacteriaceae (CRE), Acinetobacter baumannii and Pseudomonas aeruginosa on Drug Development to Meet the Challenge of Antimicrobial Resistance, September 6-8, 2017. Posters were on apramycin, inkjet printer-based susceptibility testing methodology, and MAST rapid susceptibility technology, respectively.
The manuscript highlights the remarkable activity of apramycin against multidrug-resistant, extensively drug resistant and pandrug-resistant Acinetobacter and Pseudomonas. Both organisms are significant multidrug-resistance threats. Importantly, frank resistance to apramycin was observed in < 2% of isolates. Apramycin is an aminocyclitol-based aminoglycoside that is currently approved for veterinary use. The activity in these groups of bacteria was especially notable in light of the high level of resistance of the same strain set to aminoglycosides (amikacin, gentamicin, tobramycin) approved for human use. This study complements our prior study, also published in DMID, demonstrating activity of apramycin against a high proportion of carbapenem-resistant Enterobacteriaceae strains.
Here is the link to to the STAT Madness competition: www.statnews.com/feature/stat-madness/bracket/. Please vote for BIDMC in the line up. Our research on discovery of antimicrobials targeting carbapenem-resistant Enterobacteriaceae is highlighted. See "Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae" published in Assay and Drug Development Technologies and accompanying editorial for more information."
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