Clavulanic Acid, a Novel Inhibitor of β-Lactamases

Neu, Harold C.; Fu, Kwung P.

doi:10.1128/aac.14.5.650

Cited by 217 publications

(112 citation statements)

References 16 publications

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“…As expected, added clavulanic acid produced little enhancement of penicillin inhibition when the sensitive strain was used. In fact, unlike most bacteria, N. gonorrhoeae are relatively sensitive to clavulanic acid (15), and later experiments showed that the peptidoglycan synthesis by ether-treated cells was affected in much the same way by this as by other ,B-lactam antibiotics.…”

Section: Resultsmentioning

confidence: 98%

In Vitro Synthesis of Peptidoglycan by β-Lactam-Sensitive and -Resistant Strains of Neisseria gonorrhoeae : Effects of β-Lactam and Other Antibiotics

Brown

Perkins

1979

Antimicrob Agents Chemother

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The synthesis in vitro of peptidoglycan by Neisseria gonorrhoeae was studied in organisms made permeable to nucleotide precursors by treatment with ether.Optimum synthesis occurred at 300C in tris(hydroxymethyl)aminomethane-maleate buffer (0.05 M; pH 6) in the presence of 20 mM Mg2e. The incorporation from uridine 5'-diphosphate-N-acetyl-['4C]glucosamine into peptidoglycan, measured after precipitation of the cells with trichloroacetic acid, was sensitive to the fl-lactam antibiotics, bacitracin, diumycin, and tunicamycin and relatively resistant to spectinomycin and tetracycline. Differences in sensitivity between preparations from a f-lactamase producer and a laboratory segregant derived from it were not great. Synthesized peptidoglycan was also fractionated into sodium dodecyl sulfate-soluble and -insoluble portions. ,B-Lactam antibiotics at concentrations equivalent to the minimal inhibitory concentrations for growth of the organisms did not inhibit peptidoglycan synthesis, but rather caused a small enhancement. At higher concentrations, above about 0.5 ug/ml, incorporation into sodium dodecyl sulfate-insoluble material was progressively inhibited, whereas the amount of sodium dodecyl sulfate-soluble product increased greatly, more than compensating for the loss of the precipitable fraction. Similar observations were made with three strains, and also with the ft-lactam clavulanic acid, normally considered as a f,-lactamase inhibitor rather than as itself an effective antibiotic.Until recently, gonococci had always been observed to be highly sensitive to penicillin, and even though some strains existed that were relatively more resistant this did not prevent penicillin from remaining the preferred treatment. In 1976, strains that had acquired high levels of resistance attributable to their production of a TEM-type f.-lactamase (1,18,19,26) were isolated in various parts of the world, and infections with these could no longer be treated by single massive doses of benzylpenicillin. Later evidence showed that the gene for the 13-lactamase was carried on plasmids of 4.4 x 10' daltons in some strains and 3.2 x 106 daltons in others, but that its base sequence was at least 70% similar in each case (3,21). It was, nevertheless, possible to treat infections with these strains by using fl-lactams resistant to TEM-f-lactamase, for which the fundamental attack on gonococcal wall synthesis could be expected to be the same as for penicillin. f3-Lactams are well known to interfere with the synthesis of bacterial cell walls by preventing the cross-linking of peptidoglycan (4), and there is good evidence that this mechanism is also involved in their action on gonococci (22). As in other organisms, their bactericidal effect is mediated by autolysis (22,32) which is promoted by penicillin action. To gain further insight into the precise way in which,-lactams can kill gonococci, whether or not they bear ,Blactamase genes on their plasmids, we have investigated directly the effect of these antibiotics on the in vitro biosynthesi...

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Section: Resultsmentioning

confidence: 98%

In Vitro Synthesis of Peptidoglycan by β-Lactam-Sensitive and -Resistant Strains of Neisseria gonorrhoeae : Effects of β-Lactam and Other Antibiotics

Brown

Perkins

1979

Antimicrob Agents Chemother

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“…8,9,33 HTA uses a classic Ser/His/Asp catalytic triad to promote transfer of the acetyl group from acetyl-CoA to homoserine. 18 Several studies in the past have shown a time-dependent inhibition of b-lactam and b-lactone compounds against Ser/His/Asp catalytic triad enzymes such as penicillin-binding proteins, 34 b-lactamases 23,35 and several Ser proteases. [36][37][38] On the basis of this precedent for other Ser/His/Asp catalytic triad enzymes, we reasoned that HTA might be inhibited by similar compounds that have the potential to form a covalent bond with the catalytic Ser (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

β-Lactone natural products and derivatives inactivate homoserine transacetylase, a target for antimicrobial agents

et al. 2011

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Homoserine transacetylase (HTA) catalyzes the transfer of an acetyl group from acetyl-CoA to the hydroxyl group of homoserine. This is the first committed step in the biosynthesis of methionine (Met) from aspartic acid in many fungi, Gram-positive and some Gram-negative bacteria. The enzyme is absent in higher eukaryotes and is important for microorganism growth in Met-poor environments, such as blood serum, making HTA an attractive target for new antimicrobial agents. HTA catalyzes acetyl transfer via a double displacement mechanism facilitated by a classic Ser-His-Asp catalytic triad located at the bottom of a narrow actives site tunnel. We explored the inhibitory activity of several b-lactones to block the activity of HTA. In particular, the natural product ebelactone A, a b-lactone with a hydrophobic tail was found to be a potent inactivator of HTA from Haemophilus influenzae. Synthetic analogs of ebelactone A demonstrated improved inactivation characteristics. Covalent modification of HTA was confirmed by mass spectrometry, and peptide mapping identified Ser143 as the modified residue, consistent with the known structure and mechanism of the enzyme. These results demonstrate that b-lactone inhibitors are excellent biochemical probes of HTA and potential leads for new antimicrobial agents.

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“…In the absence of beta-lactamase, a synergistic effect cannot be demonstrated (8). The susceptibility to beta-lactamase of bacteria which produce chromosomally controlled cephalosporinase with a low affinity for CA is usually not enhanced by the addition of CA (6). An interesting recent study has shown that each bacterial species may include a spectrum of susceptibility to the beta-lactamase inhibition by CA (1).…”

Section: Discussionmentioning

confidence: 99%

“…A number of in vitro experiments have shown that small amounts of CA (0.5 to 10 usg/ml) potentiate the activity of various beta-lactam antibiotics against a variety of gram-positive and gram-negative bacteria that produce a plasmid-800 HEREEMA, MUSHER, AND WILLIAMS controlled beta-lactamase (6,8,11,13). In the absence of beta-lactamase, a synergistic effect cannot be demonstrated (8).…”

Section: Discussionmentioning

confidence: 99%

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Clavulanic acid and penicillin treatment of Staphylococcus aureus renal infection in mice

Heerema¹,

Musher²,

Williams³

1979

Antimicrob Agents Chemother

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Clavulanic acid, an inhibitor of beta-lactamase, was used together with penicillin to treat infection caused by a penicillinase-producing Staphylococcus aureus. Clavulanic acid + penicillin administered to mice, prophylactically or in treatment of established infection, reduced morbidity, bacterial counts in the kidneys, and/or mortality; these differences were statistically significant when compared with those obtained by using penicillin or clavulanic acid alone.

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Clavulanic Acid, a Novel Inhibitor of β-Lactamases

Cited by 217 publications

References 16 publications

In Vitro Synthesis of Peptidoglycan by β-Lactam-Sensitive and -Resistant Strains of Neisseria gonorrhoeae : Effects of β-Lactam and Other Antibiotics

In Vitro Synthesis of Peptidoglycan by β-Lactam-Sensitive and -Resistant Strains of Neisseria gonorrhoeae : Effects of β-Lactam and Other Antibiotics

β-Lactone natural products and derivatives inactivate homoserine transacetylase, a target for antimicrobial agents

Clavulanic acid and penicillin treatment of Staphylococcus aureus renal infection in mice

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