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AIM‐1: An Antibiotic‐Degrading Metallohydrolase That Displays Mechanistic Flexibility |
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| Authors: | Christopher Selleck Prof James A Larrabee Assoc?Prof Jeffrey Harmer Assoc?Prof Luke W Guddat Dr Nata?a Miti? Waleed Helweh Prof David L Ollis Dr Whitney R Craig Prof David L Tierney Dr Marcelo Monteiro?Pedroso Prof Gerhard Schenk |
| Institution: | 1. School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia;2. Department of Chemistry and Biochemistry, Middlebury College, Middlebury, Vermont, USA;3. Centre for Advanced Imaging, The University of Queensland, St. Lucia, Queensland, Australia;4. Department of Chemistry, Maynooth University, Maynooth, Co., Kildare, Ireland;5. Research School of Chemistry, Australian National University of Canberra, ACT, Australia;6. Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA |
| 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. |
| Keywords: | antibiotic resistance imipenemase β -lactam antibiotics metalloenzyme metallo-β -lactamase |