Advertisement

New promising β-lactamase inhibitors for clinical use

  • I. OlsenEmail author
Review

Abstract

Clavulanate, sulbactam, and tazobactam have been used extensively for the last 30 years, together with β-lactam antibiotics, to inhibit the effect of β-lactamases. Although they have been useful as β-lactamase inhibitors in many cases, their effectiveness is restricted to class A β-lactamases. With the increasing frequency and breadth of β-lactamases now threatening public health throughout the world, we need a much broader spectrum of β-lactamase inhibitors efficient against all classes of β-lactamases. There are several β-lactamase inhibitors under development, but only a few of them are able to inhibit class D and even fewer class B metallo-β-lactamases (MβLs). The latter represent a real threat to the latest generations of β-lactam antibiotics, including cephalosporins and carbapenems. Only two β-lactamase inhibitors are, so far, under clinical evaluation, i.e., avibactam and MK-7655. The others are years from being clinically available. Although this has caused cautious optimism, the progress in this field is far too slow. This is particularly so because none of the substances provided are active against MβLs and because new β-lactamases invariably force their way into our therapeutic armamentarium. While waiting for new antibiotics and new β-lactamase inhibitors to become available, it is important to carry out accurate clinical and microbiological diagnosis, perform adequate hygiene, and use antibiotics properly. This may save lives and reduce resistance resulting from inappropriate antibiotic treatment.

Keywords

Ceftazidime Imipenem Carbapenems Clavulanic Acid Aztreonam 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The author was funded through a grant from the European Commission (FP7-HEALTH-30609 “TRIGGER”).

Conflict of interest

The author has no commercial relationships and no potential conflicts of interest. The article does not contain any studies with human participants or animals performed by the author. The article does not contain patient data.

References

  1. 1.
    Lahiri SD, Mangani S, Durand-Reville T, Benvenuti M, De Luca F, Sanyal G, Docquier JD (2013) Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC β-lactamases. Antimicrob Agents Chemother 57(6):2496–2505PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Livermore DM (1995) β-Lactamases in laboratory and clinical resistance. Clin Microbiol Rev 8(4):557–584PubMedCentralPubMedGoogle Scholar
  3. 3.
    Ambler RP (1980) The structure of beta-lactamases. Philos Trans R Soc Lond B Biol Sci 289(1036):321–331PubMedCrossRefGoogle Scholar
  4. 4.
    Bush K, Jacoby GA, Medeiros AA (1995) A functional classification scheme for beta-lactamases and its correlation with molecular structure. Antimicrob Agents Chemother 39(6):1211–1233PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Bush K, Jacoby GA (2010) Updated functional classification of β-lactamases. Antimicrob Agents Chemother 54(3):969–976PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Watkins RR, Papp-Wallace KM, Drawz SM, Bonomo RA (2013) Novel β-lactamase inhibitors: a therapeutic hope against the scourge of multidrug resistance. Front Microbiol 4:392PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Palzkill T (2013) Metallo-β-lactamase structure and function. Ann N Y Acad Sci 1277:91–104PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Ghafourian S, Sadeghifard N, Soheili S, Sekawi Z (2014) Extended spectrum beta-lactamases: definition, classification and epidemiology. Curr Issues Mol Biol 17:11–22PubMedGoogle Scholar
  9. 9.
    Bradford PA (2001) Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev 14(4):933–951PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Paterson DL, Bonomo RA (2005) Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev 18(4):657–686PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Søraas A, Olsen I, Sundsfjord A, Handal T, Bjørang O, Jenum PA (2014) Extended-spectrum beta-lactamase-producing bacteria are not detected in supragingival plaque samples from human fecal carriers of ESBL-producing Enterobacteriaceae. J Oral Microbiol 6:24026. doi: 10.3402/jom.v6.24026 CrossRefGoogle Scholar
  12. 12.
    Keating TA, Lister T, Verheijen JC (2014) New antibacterial agents: patent applications published in 2011. Pharm Pat Anal 3(1):87–112PubMedCrossRefGoogle Scholar
  13. 13.
    Drawz SM, Papp-Wallace KM, Bonomo RA (2014) New β-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother 58(4):1835–1846PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Buynak JD (2013) β-Lactamase inhibitors: a review of the patent literature (2010–2013). Expert Opin Ther Pat 23(11):1469–1481PubMedCrossRefGoogle Scholar
  15. 15.
    Chen J, Shang X, Hu F, Lao X, Gao X, Zheng H, Yao W (2013) β-Lactamase inhibitors: an update. Mini Rev Med Chem 13(13):1846–1861PubMedCrossRefGoogle Scholar
  16. 16.
    Karpiuk I, Tyski S (2013) Looking for the new preparations for antibacterial therapy. II. Clinical trials; new β-lactam antibiotics and β-lactamase inhibitors. Przegl Epidemiol 67(1):51–56, 135–140PubMedGoogle Scholar
  17. 17.
    Biondi S, Long S, Panunzio M, Qin WL (2011) Current trends in β-lactam based β-lactamases inhibitors. Curr Med Chem 18(27):4223–4236PubMedCrossRefGoogle Scholar
  18. 18.
    Pucci MJ, Page MGP, Bush K (2014) Cautious optimism for the antibacterial pipeline. Microbe 9(4):147–152Google Scholar
  19. 19.
    Drawz SM, Bonomo RA (2010) Three decades of β-lactamase inhibitors. Clin Microbiol Rev 23(1):160–201PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Coleman K (2011) Diazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitors. Curr Opin Microbiol 14(5):550–555PubMedCrossRefGoogle Scholar
  21. 21.
    Ehmann DE, Jahić H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL (2012) Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A 109(29):11663–11668PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Zhanel GG, Lawson CD, Adam H, Schweizer F, Zelenitsky S, Lagacé-Wiens PR, Denisuik A, Rubinstein E, Gin AS, Hoban DJ, Lynch JP 3rd, Karlowsky JA (2013) Ceftazidime–avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs 73(2):159–177PubMedCrossRefGoogle Scholar
  23. 23.
    Livermore DM, Mushtaq S, Warner M, Zhang J, Maharjan S, Doumith M, Woodford N (2011) Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother 55(1):390–394PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Mushtaq S, Warner M, Livermore DM (2010) In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters. J Antimicrob Chemother 65(11):2376–2381PubMedCrossRefGoogle Scholar
  25. 25.
    Goldstein EJC, Citron DM, Merriam CV, Tyrrell KL (2013) Comparative in vitro activity of ceftaroline, ceftaroline–avibactam, and other antimicrobial agents against aerobic and anaerobic bacteria cultured from infected diabetic foot wounds. Diagn Microbiol Infect Dis 76(3):347–351PubMedCrossRefGoogle Scholar
  26. 26.
    Livermore DM, Mushtaq S (2013) Activity of biapenem (RPX2003) combined with the boronate β-lactamase inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae. J Antimicrob Chemother 68(8):1825–1831PubMedCrossRefGoogle Scholar
  27. 27.
    Morandi S, Morandi F, Caselli E, Shoichet BK, Prati F (2008) Structure-based optimization of cephalothin-analogue boronic acids as beta-lactamase inhibitors. Bioorg Med Chem 16(3):1195–1205PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Goldstein EJC, Citron DM, Tyrrell KL, Merriam CV (2013) In vitro activity of Biapenem plus RPX7009, a carbapenem combined with a serine β-lactamase inhibitor, against anaerobic bacteria. Antimicrob Agents Chemother 57(6):2620–2630PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Blizzard TA, Chen H, Kim S, Wu J, Young K, Park YW, Ogawa A, Raghoobar S, Painter RE, Hairston N, Lee SH, Misura A, Felcetto T, Fitzgerald P, Sharma N, Lu J, Ha S, Hickey E, Hermes J, Hammond ML (2010) Side chain SAR of bicyclic β-lactamase inhibitors (BLIs). 1. Discovery of a class C BLI for combination with imipinem. Bioorg Med Chem Lett 20(3):918–921PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Oral Biology, Faculty of DentistryUniversity of OsloOsloNorway

Personalised recommendations