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Structural/mechanistic insights into the efficacy of nonclassical β-lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates.

Calvopiña K, Hinchliffe P, Brem J, Heesom KJ, Johnson S, Cain R, Lohans CT, Fishwick CWG, Schofield CJ, Spencer J, Avison MB
Mol Microbiol 106 492-504 (2017)
Related entries: 5ne1, 5ne3

Cited: 26 times
EuropePMC logo PMID: 28876489

Abstract

Clavulanic acid and avibactam are clinically deployed serine β-lactamase inhibitors, important as a defence against antibacterial resistance. Bicyclic boronates are recently discovered inhibitors of serine and some metallo β-lactamases. Here, we show that avibactam and a bicyclic boronate inhibit L2 (serine β-lactamase) but not L1 (metallo β-lactamase) from the extensively drug resistant human pathogen Stenotrophomonas maltophilia. X-ray crystallography revealed that both inhibitors bind L2 by covalent attachment to the nucleophilic serine. Both inhibitors reverse ceftazidime resistance in S. maltophilia because, unlike clavulanic acid, they do not induce L1 production. Ceftazidime/inhibitor resistant mutants hyperproduce L1, but retain aztreonam/inhibitor susceptibility because aztreonam is not an L1 substrate. Importantly, avibactam, but not the bicyclic boronate is deactivated by L1 at a low rate; the utility of avibactam might be compromised by mutations that increase this deactivation rate. These data rationalize the observed clinical efficacy of ceftazidime/avibactam plus aztreonam as combination therapy for S. maltophilia infections and confirm that aztreonam-like β-lactams plus nonclassical β-lactamase inhibitors, particularly avibactam-like and bicyclic boronate compounds, have potential for treating infections caused by this most intractable of drug resistant pathogens.

Reviews - 5ne2 mentioned but not cited (1)

  1. The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases. Egorov A, Rubtsova M, Grigorenko V, Uporov I, Veselovsky A. Biomolecules 9 E854 (2019)

Articles - 5ne2 mentioned but not cited (1)

  1. Molecular Basis of Class A β-Lactamase Inhibition by Relebactam. Tooke CL, Hinchliffe P, Lang PA, Mulholland AJ, Brem J, Schofield CJ, Spencer J. Antimicrob Agents Chemother 63 e00564-19 (2019)


Reviews citing this publication (5)

  1. β-Lactamases and β-Lactamase Inhibitors in the 21st Century. Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VHA, Takebayashi Y, Spencer J. J Mol Biol 431 3472-3500 (2019)
  2. Will morphing boron-based inhibitors beat the β-lactamases? Krajnc A, Lang PA, Panduwawala TD, Brem J, Schofield CJ. Curr Opin Chem Biol 50 101-110 (2019)
  3. Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches. van den Akker F, Bonomo RA. Front Microbiol 9 622 (2018)
  4. Antimicrobial Treatment Strategies for Stenotrophomonas maltophilia: A Focus on Novel Therapies. Gibb J, Wong DW. Antibiotics (Basel) 10 1226 (2021)
  5. The biogenesis of β-lactamase enzymes. Kaderabkova N, Bharathwaj M, Furniss RCD, Gonzalez D, Palmer T, Mavridou DAI. Microbiology (Reading) 168 (2022)

Articles citing this publication (19)

  1. Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases. Krajnc A, Brem J, Hinchliffe P, Calvopiña K, Panduwawala TD, Lang PA, Kamps JJAG, Tyrrell JM, Widlake E, Saward BG, Walsh TR, Spencer J, Schofield CJ. J Med Chem 62 8544-8556 (2019)
  2. Mutation-Driven Evolution of Pseudomonas aeruginosa in the Presence of either Ceftazidime or Ceftazidime-Avibactam. Sanz-García F, Hernando-Amado S, Martínez JL. Antimicrob Agents Chemother 62 e01379-18 (2018)
  3. Advances in the Microbiology of Stenotrophomonas maltophilia. Brooke JS. Clin Microbiol Rev 34 e0003019 (2021)
  4. Structural and Kinetic Studies of the Potent Inhibition of Metallo-β-lactamases by 6-Phosphonomethylpyridine-2-carboxylates. Hinchliffe P, Tanner CA, Krismanich AP, Labbé G, Goodfellow VJ, Marrone L, Desoky AY, Calvopiña K, Whittle EE, Zeng F, Avison MB, Bols NC, Siemann S, Spencer J, Dmitrienko GI. Biochemistry 57 1880-1892 (2018)
  5. Mechanism of proton transfer in class A β-lactamase catalysis and inhibition by avibactam. Pemberton OA, Noor RE, Kumar M V V, Sanishvili R, Kemp MT, Kearns FL, Woodcock HL, Gelis I, Chen Y. Proc Natl Acad Sci U S A 117 5818-5825 (2020)
  6. Escape mutations circumvent a tradeoff between resistance to a beta-lactam and resistance to a beta-lactamase inhibitor. Russ D, Glaser F, Shaer Tamar E, Yelin I, Baym M, Kelsic ED, Zampaloni C, Haldimann A, Kishony R. Nat Commun 11 2029 (2020)
  7. Activity of Aztreonam in Combination with Avibactam, Clavulanate, Relebactam, and Vaborbactam against Multidrug-Resistant Stenotrophomonas maltophilia. Biagi M, Lamm D, Meyer K, Vialichka A, Jurkovic M, Patel S, Mendes RE, Bulman ZP, Wenzler E. Antimicrob Agents Chemother 64 e00297-20 (2020)
  8. Profiling interactions of vaborbactam with metallo-β-lactamases. Langley GW, Cain R, Tyrrell JM, Hinchliffe P, Calvopiña K, Tooke CL, Widlake E, Dowson CG, Spencer J, Walsh TR, Schofield CJ, Brem J. Bioorg Med Chem Lett 29 1981-1984 (2019)
  9. Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli. Lang PA, Parkova A, Leissing TM, Calvopiña K, Cain R, Krajnc A, Panduwawala TD, Philippe J, Fishwick CWG, Trapencieris P, Page MGP, Schofield CJ, Brem J. Biomolecules 10 E899 (2020)
  10. Cyclic boronates as versatile scaffolds for KPC-2 β-lactamase inhibition. Tooke CL, Hinchliffe P, Krajnc A, Mulholland AJ, Brem J, Schofield CJ, Spencer J. RSC Med Chem 11 491-496 (2020)
  11. Disruption of mpl Activates β-Lactamase Production in Stenotrophomonas maltophilia and Pseudomonas aeruginosa Clinical Isolates. Calvopiña K, Avison MB. Antimicrob Agents Chemother 62 e00638-18 (2018)
  12. Stenotrophomonas maltophilia Susceptibility Testing Challenges and Strategies. Rhoads DD. J Clin Microbiol 59 e0109421 (2021)
  13. 2-Mercaptomethyl Thiazolidines (MMTZs) Inhibit All Metallo-β-Lactamase Classes by Maintaining a Conserved Binding Mode. Hinchliffe P, Moreno DM, Rossi MA, Mojica MF, Martinez V, Villamil V, Spellberg B, Drusano GL, Banchio C, Mahler G, Bonomo RA, Vila AJ, Spencer J. ACS Infect Dis 7 2697-2706 (2021)
  14. Molecular Basis for the Potent Inhibition of the Emerging Carbapenemase VCC-1 by Avibactam. Mangat CS, Vadlamani G, Holicek V, Chu M, Larmour VLC, Vocadlo DJ, Mulvey MR, Mark BL. Antimicrob Agents Chemother 63 e02112-18 (2019)
  15. A proteomics-based method for identifying antigens within immune complexes. Menikou S, McArdle AJ, Li MS, Kaforou M, Langford PR, Levin M. PLoS One 15 e0244157 (2020)
  16. Exploring Covalent Docking Mechanisms of Boron-Based Inhibitors to Class A, C and D β-Lactamases Using Time-dependent Hybrid QM/MM Simulations. Charzewski Ł, Krzyśko KA, Lesyng B. Front Mol Biosci 8 633181 (2021)
  17. Aztreonam-avibactam synergy, a validation and comparison of diagnostic tools. Verschelden G, Noeparast M, Stoefs A, Van Honacker E, Vandoorslaer K, Vandervore L, Olbrecht M, Van Damme K, Demuyser T, Piérard D, Wybo I. Front Microbiol 14 1322180 (2023)
  18. Enhancement and Comparison of (Ceftazidime-)Avibactam Plus Aztreonam Susceptibility Tests for Stenotrophomonas maltophilia in Clinical Diagnostics. Vlaspolder GL, Hughes LA, Huis In 't Veld RAG, Kampinga GA, Bathoorn E. Curr Microbiol 81 28 (2023)
  19. Interactions of hydrolyzed β-lactams with the L1 metallo-β-lactamase: Crystallography supports stereoselective binding of cephem/carbapenem products. Hinchliffe P, Calvopiña K, Rabe P, Mojica MF, Schofield CJ, Dmitrienko GI, Bonomo RA, Vila AJ, Spencer J. J Biol Chem 299 104606 (2023)


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