1887

Abstract

The quantities of penicillin-binding proteins (PBPs), and sensitivity to extended-spectrum -lactams, were measured in isogenic strains of with high (HR) and low (LR) resistance to extended-spectrum -lactam antibiotics and with constitutively overproduced chromosomal -lactamase in the periplasm. The binding of structurally different -lactams to PBPs in growing resistant bacteria was determined quantitatively. In HR, the amounts of PBPs 3 and 6 were, respectively, 1·5 and 2 times those in strain LR and in sensitive reference strains. Sensitivities of the essential PBPs in LR and HR to the tested -lactams were identical. Only a single target, PBP 3, was highly sensitive to cefotaxime, ceftazidime and aztreonam. In contrast, three PBPs (2, 1A and 3) were highly sensitive to imipenem. In growing HR and LR, all antibiotics, even at fractions of their minimal growth inhibitory concentrations (MICs), bound extensively to those PBPs which were highly sensitive to them. Thus, overproduced -lactamase did not prevent PBP--lactam interaction. Only at or above their (high) MICs did cefotaxime, ceftazidime and aztreonam bind to multiple targets. Growth inhibition of the otherwise highly resistant HR at the lower MIC of imipenem was correlated with the binding of this antibiotic to multiple, highly sensitive targets in the bacteria. Killing of the bacteria by inactivation of multiple targets was suggested. This assumption was supported by the synergistic killing of HR bacteria by combinations of the PBP-2-specific mecillinam with PBP-3-specific -lactams.

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1991-02-01
2021-10-16
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References

  1. Baltimore R. S., Klein J. O., Wilcox C., Finland M. 1976; Synergy of mecillinam (FL1060) with penicillins and cephalosporins against Proteus and Klebsiella with observations on combinations with other antibiotics and against other bacterial species.. Antimicrobial Agents and Chemotherapy 9:701–705
    [Google Scholar]
  2. Buscher K. H., Cullmann W., Dick W., Opferkuch W. 1987; Imipenem resistance in Pseudomonas aeruginosa resulting from diminished expression of an outer membrane protein.. Antimicrobial Agents and Chemotherapy 31:703–708
    [Google Scholar]
  3. Bush K., Tanaka S. K., Bonner D. P., Sykes R. B. 1985; Resistance caused by decreased penetration of β-lactam antibiotics into Enterobacter cloacae . Antimicrobial Agents and Chemotherapy 27:555–560
    [Google Scholar]
  4. Chase H. A., Fuller C., Reynolds P. E. 1981; The role of penicillin-binding proteins in the action of cephalosporins against Escherichia coli and Salmonella typhimurium . European Journal of Biochemistry 117:301–310
    [Google Scholar]
  5. Curtis N. A. C, Orr D., Ross G. W., Boulton M. G. 1979; Competition of β-lactam antibiotics for the penicillin-binding proteins of Pseudomonas aeruginosa, Enterobacter cloacae, Klebsiella aerogenes, Proteus rettgeri and Escherichia coli: comparison with antibacterial activity and effects upon bacterial morphology.. Antimicrobial Agents and Chemotherapy 16:325–328
    [Google Scholar]
  6. De Meester F., Frère J. M., Waley S. G., Cartwright S. G., Virden R., Lindberg F. 1986; 6-β-Iodopenicillinate as a probe for the classification of β-lactamases.. Biochemical Journal 239:575–580
    [Google Scholar]
  7. Frère J. M. 1989; Quantitative relationship between sensitivity to β-lactam antibiotics and β-lactamase production in Gram-negative bacteria - I. Steady state treatment.. Biochemical Pharmacology 38:1415–1426
    [Google Scholar]
  8. Frère J. M., Joris B. 1985; Penicillin-sensitive enzymes in peptidoglycan synthesis.. CRC Critical Reviews in Microbiology 11:299–396
    [Google Scholar]
  9. Frère J. M., Joris B., Crine M., Martin H. H. 1989; Quantitative relationship between sensitivity to β-lactam antibiotics and β-lactamase production in Gram-negative bacteria. II. Non-steady-state treatment and progress curves.. Biochemical Pharmacology 38:1427–1433
    [Google Scholar]
  10. Georgopapadakou N. H. 1988; Penicillin-binding proteins. Antimicrobial Agents Annual 3409–431 Peterson P. K., Verhoef. J. Amsterdam: Elsevier Science Publishers;
    [Google Scholar]
  11. Ghuysen J. M., Frère J. M., Leyh-Bouille M., Nguyen-Disteche M., Coyette J. 1986; Active-site-serine d-alanyl-d-alanine-cleaving-peptidases-catalysed acyl-transfer reactions. Procedures for studying the penicillin-binding proteins of bacterial plasma membranes.. Biochemical Journal 235:159–165
    [Google Scholar]
  12. Godfrey A. J., Bryan L. E., Rabin H. R. 1981; β-Lactam-resistant Pseudomonas aeruginosa with modified penicillin-binding proteins emerging during cystic fibrosis treatment.. Antimicrobial Agents and Chemotherapy 19:705–711
    [Google Scholar]
  13. Gutmann L., Chabbert Y. A. 1984; Different mechanisms of resistance to latamoxef (moxalactam) in Serratia marcescens . Journal of Antimicrobial Chemotherapy 13:15–22
    [Google Scholar]
  14. Gutmann L., Vincent S., Billot-Klein D., Acar J. F., Mrena E., Williamson R. 1986; Involvment of penicillin-binding protein 2 with other penicillin-binding proteins in lysis of Escherichia coli by some β-lactam antibiotics alone and in synergistic lytic effect of amdinocillin (mecillinam).. Antimicrobial Agents and Chemotherapy 30:906–912
    [Google Scholar]
  15. Hechler U., Van den Weghe M., Martin H. H., Frère J. M. 1989; Overproduced β-lactamase and the outer membrane barrier as resistance factors in Serratia marcescens highly resistant to β-lactamase-stable β-lactam antibiotics.. Journal of General Microbiology 135:1275–1290
    [Google Scholar]
  16. Jack G. W., Richmond M. H. 1970; A comparative study of eight different β-lactamases synthesized by Gram-negative bacteria.. Journal of General Microbiology 61:43–61
    [Google Scholar]
  17. Krogstad D. J., Moellering R. C Jr. 1980; Combinations of antibiotics, mechanisms of interaction against bacteria.. In Anti-biotics in Laboratory Medicine298–341 Lorian. V. Baltimore London: Williams Wilkins;
    [Google Scholar]
  18. Lugtenberg B., Van Alphen L. 1983; Molecular architecture and functioning of the outer membrane of Escherichia coli and other Gram-negative bacteria.. Biochimica et Biophysica Acta 737:51–115
    [Google Scholar]
  19. Marchou B., Bellido F., Charnas R., Lucain C., Pechere J. C. 1987; Contribution of β-lactamase hydrolysis and outer membrane permeability to ceftriaxone resistance in Enterobacter cloacae . Antimicrobial Agents and Chemotherapy 31:1589–1595
    [Google Scholar]
  20. Miller J. H. 1972 Experiments in Molecular Genetics. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory.;
    [Google Scholar]
  21. Neu H. C. 1976; Synergy of mecillinam, a beta-amidinopenicillanic acid derivative, combined with beta-lactam antibiotics.. Antimicrobial Agents and Chemotherapy 10:535–542
    [Google Scholar]
  22. Nikaido H. 1989; Outer membrane barrier as mechanism of antimicrobial resistance.. Antimicrobial Agents and Chemotherapy 33:1831–1836
    [Google Scholar]
  23. Nikaido H., Normark S. 1987; Sensitivity of Escherichia coli to various β-lactams is determined by the interplay of outer membrane permeability and degradation by periplasmic β-lactamases: a quantitative predictive treatment.. Molecular Microbiology 1:29–36
    [Google Scholar]
  24. Spratt B. G. 1975; Distinct penicillin-binding proteins involved in the division, elongation, and shape of Escherichia coli K12.. Proceedings of the National Academy of Sciences of the United States of America 722999–3003
    [Google Scholar]
  25. Spratt B. G. 1977; Properties of the penicillin-binding proteins of Escherichia coli K12.. European Journal of Biochemistry 72:341–352
    [Google Scholar]
  26. Spratt B. G., Jobanputra V., Zimmermann W. 1977; Binding of thienamycin and clavulanic acid to the penicillin-binding proteins of Escherichia coli K12.. Antimicrobial Agents and Chemotherapy 12:406–409
    [Google Scholar]
  27. Then R. L., Angehrn P. 1986; Multiply resistant mutants of Enterobacter cloacae selected by β-lactam antibiotics.. Antimicrobial Agents and Chemotherapy 30:684–688
    [Google Scholar]
  28. Tybring L., Melchior N. H. 1975; Mecillinam (FL1060), a 6-β-amidinopenicillanic acid derivative: bactericidal action and synergy in vitro . Antimicrobial Agents and Chemotherapy 8:271–276
    [Google Scholar]
  29. Vu H., Nikaido H. 1985; Role of β-lactam hydrolysis in the mechanism of resistance of a β-lactamase-constitutive Enterobacter cloacae strain to expanded-spectrum β-lactams.. Antimicrobial Agents and Chemotherapy 27:393–398
    [Google Scholar]
  30. Werner V., Sanders C. C, Sanders W. E. Jr, Goering R. V. 1985; Role of β-lactamases and outer membrane proteins in multiple β-lactam resistance of Entgerobacter cloacae . Antimicrobial Agents and Chemotherapy 27:455–459
    [Google Scholar]
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