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      β-Lactam Antibiotics Renaissance

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          Abstract

          Since the 1940s β-lactam antibiotics have been used to treat bacterial infections. However, emergence and dissemination of β-lactam resistance has reached the point where many marketed β-lactams no longer are clinically effective. The increasing prevalence of multidrug-resistant bacteria and the progressive withdrawal of pharmaceutical companies from antibiotic research have evoked a strong reaction from health authorities, who have implemented initiatives to encourage the discovery of new antibacterials. Despite this gloomy scenario, several novel β-lactam antibiotics and β-lactamase inhibitors have recently progressed into clinical trials, and many more such compounds are being investigated. Here we seek to provide highlights of recent developments relating to the discovery of novel β-lactam antibiotics and β-lactamase inhibitors.

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          Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor.

          David E Ehmann, Mary Ross, G K Walkup … (2012)
          Avibactam is a β-lactamase inhibitor that is in clinical development, combined with β-lactam partners, for the treatment of bacterial infections comprising gram-negative organisms. Avibactam is a structural class of inhibitor that does not contain a β-lactam core but maintains the capacity to covalently acylate its β-lactamase targets. Using the TEM-1 enzyme, we characterized avibactam inhibition by measuring the on-rate for acylation and the off-rate for deacylation. The deacylation off-rate was 0.045 min(-1), which allowed investigation of the deacylation route from TEM-1. Using NMR and MS, we showed that deacylation proceeds through regeneration of intact avibactam and not hydrolysis. Other than TEM-1, four additional clinically relevant β-lactamases were shown to release intact avibactam after being acylated. We showed that avibactam is a covalent, slowly reversible inhibitor, which is a unique mechanism of inhibition among β-lactamase inhibitors.
          Article 0 comments Cited 140 times – based on 0 reviews     Review now
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            Fix the antibiotics pipeline.

            Matthew A. Cooper, David M Shlaes (2011)
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              Kinetics of avibactam inhibition against Class A, C, and D β-lactamases.

              David E Ehmann, Haris Jahić, Philip L Ross … (2013)
              Avibactam is a non-β-lactam β-lactamase inhibitor with a spectrum of activity that includes β-lactamase enzymes of classes A, C, and selected D examples. In this work acylation and deacylation rates were measured against the clinically important enzymes CTX-M-15, KPC-2, Enterobacter cloacae AmpC, Pseudomonas aeruginosa AmpC, OXA-10, and OXA-48. The efficiency of acylation (k2/Ki) varied across the enzyme spectrum, from 1.1 × 10(1) m(-1)s(-1) for OXA-10 to 1.0 × 10(5) for CTX-M-15. Inhibition of OXA-10 was shown to follow the covalent reversible mechanism, and the acylated OXA-10 displayed the longest residence time for deacylation, with a half-life of greater than 5 days. Across multiple enzymes, acyl enzyme stability was assessed by mass spectrometry. These inhibited enzyme forms were stable to rearrangement or hydrolysis, with the exception of KPC-2. KPC-2 displayed a slow hydrolytic route that involved fragmentation of the acyl-avibactam complex. The identity of released degradation products was investigated, and a possible mechanism for the slow deacylation from KPC-2 is proposed.
              Article 0 comments Cited 113 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Antibiotics (Basel)
                Journal ID (iso-abbrev): Antibiotics (Basel)
                Journal ID (publisher-id): antibiotics
                Title: Antibiotics
                Publisher: MDPI
                ISSN (Electronic): 2079-6382
                Publication date (Electronic): 09 May 2014
                Publication date Collection: June 2014
                Volume: 3
                Issue: 2
                Pages: 193-215
                Affiliations
                [1 ]ISOF-CNR Department of Chemistry “G. Ciamician”, Via Selmi, 2 I-40126 Bologna, Italy; E-Mail: wenling.qin2@ 123456unibo.it
                [2 ]Allecra Therapeutics SAS, 13, rue de Village-Neuf, F-68300 St-Louis, France
                Author notes
                [* ]Authors to whom correspondence should be addressed; E-Mails: mauro.panunzio@ 123456unibo.it (M.P.); sdb@ 123456allecra.com (S.B.); Tel./Fax: +39-051-209-9508 (M.P.); Tel.:+33-389-689-876 (S.B.).
                Article
                Publisher ID: antibiotics-03-00193
                DOI: 10.3390/antibiotics3020193
                PMC ID: 4790388
                PubMed ID: 27025744
                SO-VID: 423b929e-5df1-4d99-b1a0-08ccad4159de
                Copyright © © 2014 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 05 March 2014
                Date revision received : 30 April 2014
                Date accepted : 04 May 2014
                Categories
                Subject: Review

                Keywords: β-lactam antibiotics,β-lactamase inhibitors,bacterial infections
                Data availability:
                Keywords: β-lactam antibiotics, β-lactamase inhibitors, bacterial infections

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