title: AIM-1: An Antibiotic-Degrading Metallohydrolase That Displays Mechanistic Flexibility.
abstract: Antibiotic resistance has emerged as a major threat to global health care. This is largely due to the fact that many pathogens have developed strategies to acquire resistance to antibiotics. Metallo-β-lactamases (MBL) have evolved to inactivate most of the commonly used β-lactam antibiotics. AIM-1 is one of only a few MBLs from the B3 subgroup that is encoded on a mobile genetic element in a major human pathogen. Here, its mechanism of action was characterised with a combination of spectroscopic and kinetic techniques and compared to that of other MBLs. Unlike other MBLs it appears that AIM-1 has two avenues available for the turnover of the substrate nitrocefin, distinguished by the identity of the rate-limiting step. This observation may be relevant with respect to inhibitor design for this group of enzymes as it demonstrates that at least some MBLs are very flexible in terms of interactions with substrates and possibly inhibitors.
authors: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, 4072, Australia.
authors: Christopher
authors: C
authors: Selleck
authors: Department of Chemistry and Biochemistry, Middlebury College, Middlebury, Vermont, 05753, USA.
authors: James A
authors: JA
authors: Larrabee
authors: Centre for Advanced Imaging, The University of Queensland, St. Lucia, Queensland, 4072, Australia.
authors: Jeffrey
authors: J
authors: Harmer
authors: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, 4072, Australia.
authors: Luke W
authors: LW
authors: Guddat
authors: Department of Chemistry, Maynooth University, Maynooth, Co., Kildare, Ireland.
authors: Nataša
authors: N
authors: Mitić
authors: Department of Chemistry and Biochemistry, Middlebury College, Middlebury, Vermont, 05753, USA.
authors: Waleed
authors: W
authors: Helweh
authors: Research School of Chemistry, Australian National University of Canberra, ACT, 0200, Australia.
authors: David L
authors: DL
authors: Ollis
authors: Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, 45056, USA.
authors: Whitney R
authors: WR
authors: Craig
authors: Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, 45056, USA.
authors: David L
authors: DL
authors: Tierney
authors: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, 4072, Australia.
authors: Marcelo
authors: M
authors: Monteiro Pedroso
authors: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, 4072, Australia.
authors: Gerhard
authors: http://orcid.org/0000-0001-8619-0631
authors: G
authors: Schenk
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D064107:Aurora Kinase B / Q000737:chemistry* / Q000378:metabolism; D002511:Cephalosporins / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D013379:Substrate Specificity; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C576921:AURKB protein, human; D064107:Aurora Kinase B; D001618:beta-Lactamases; C021720:nitrocefin
keywords: antibiotic resistance; imipenemase; metallo-β-lactamase; metalloenzyme; β-lactam antibiotics