title: Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance.
abstract: The emergence and spread of carbapenem-resistant Gram-negative pathogens is a global public health problem. The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. To date, a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems has not been found. Here we have identified a fungal natural product, aspergillomarasmine A (AMA), that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-type alleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae, AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL-positive carbapenem-resistant Gram-negative pathogens.
authors: 1] M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada [2] Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors: Andrew M
authors: AM
authors: King
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors: Sarah A
authors: SA
authors: Reid-Yu
authors: M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors: Wenliang
authors: W
authors: Wang
authors: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors: Dustin T
authors: DT
authors: King
authors: M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors: Gianfranco
authors: G
authors: De Pascale
authors: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors: Natalie C
authors: NC
authors: Strynadka
authors: Cardiff Institute of Infection & Immunity, Cardiff University, Cardiff CF14 4XN, UK.
authors: Timothy R
authors: TR
authors: Walsh
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors: Brian K
authors: BK
authors: Coombes
authors: 1] M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada [2] Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada [3] Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors: Gerard D
authors: GD
authors: Wright
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D001230:Aspergillus / Q000737:chemistry; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology; D015780:Carbapenems / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D000077731:Meropenem; D051379:Mice; D013845:Thienamycins / Q000494:pharmacology*; D018440:beta-Lactam Resistance / Q000187:drug effects*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D015780:Carbapenems; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D001224:Aspartic Acid; C069862:aspergillomarasmine A; C417264:VIM-1 metallo-beta-lactamase; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D000077731:Meropenem