Azospirillum lipoferum RG20, a nitrogen-fixing bacterium found in all kind of soils, was found to be naturally resistant to penicillins and cephalosporins. 6-beta-Bromopenicillanic acid, an irreversible inhibitor of serine-beta-lactamases, completely abolished this resistance. A beta-lactamase was purified 518-fold from a cell-free extract of A. lipoferum RG20. A single band on SDS-PAGE (apparent molecular mass 31000 Da) and on isoelectric focussing (pI9.35) was observed with the purified protein. The enzyme hydrolysed benzylpenicillin, ampicillin, cephalothin and cephaloridine with comparable k(cat) values and catalytic efficiencies. However, carbenicillin and cefotaxime were hydrolysed with significantly lower kinetic parameters and oxacillin was hydrolysed at a rate 100 times slower. The purified beta-lactamase was inhibited by clavulanic acid and sulbactam but not by EDTA or aztreonam. Its substrate and inhibitor profiles are consistent with those of the broad-spectrum beta-lactamases inhibited by clavulanic acid (group 2b of the Bush-Jacoby-Medeiros scheme). The effect of pH on k(cat) and K(m) values for benzylpenicillin hydrolysis was studied. The dependence of k(cat) on pH suggests that the enzyme-substrate (ES) complex must be in at least three protonation states: two with k(cat) values equal to 2800 and 1450 s(-1) and a third inactive one [pK(1(ES)) 4.7 and pK(2(ES)) 7.9]. Similarly, the dependence of k(cat)/K(m) on pH can be explained by postulating that the enzyme free form can be at least in three different protonation states: two of them with k(cat)/K(m) values equal to 2.7 x 10(6) and 3.7 x 10(8) M(-1) s(-1) and a third one unable to productively bind substrate. Interestingly, the dependence of k(cat)/K(m) on pH is consistent with positive cooperativity for proton binding to the enzyme free form [pK(1(E)) 8.5 and pK(2(E)) 7.2].

01 Feb 1998·Journal of Antimicrobial ChemotherapyQ2 · MEDICINE

Comparative in-vitro activities of GD-40 and other beta-lactamase inhibitors against TEM-1 and SHV-2 beta-lactamases

Q2 · MEDICINE

Letter

Author: Mata, Ernesto G. ; Del Lujan Calcagno, Maria ; Mascaretti, Oreste ; Power, Pablo ; Radice, Marcela ; Danelon, Gerardo ; Gutkind, Gabriel

The IC₅₀s of GD-40 were comparable to those of earlier β-lactamase inhibitors (clavulanic acid and sulbactam) and higher than those of more recently introduced compounds (tazobactam and brobactam) against TEM-1 and SHV-2 β-lactamases obtained from Escherichia coli strains.Thus, GD-40 and other 6α-halo-2β-chloromethylsulfones may be of value as inhibitors of both broad- and extended-spectrum β-lactamases.

01 Feb 1997·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Properties of IRT-14 (TEM-45), a newly characterized mutant of TEM-type beta-lactamases

Q2 · MEDICINE

Article

Author: Gilly, L ; Paul, G ; Barthélémy, M ; Labia, R ; Krishnamoorthy, R ; Caniça, M M

IRT-14 (TEM-45) is a new mutant TEM-type beta-lactamase that was isolated from clinical Escherichia coli P37 and that confers resistance to broad-spectrum penicillins with reduced sensitivity to beta-lactamase inhibitors. The MICs of amoxicillin alone and of amoxicillin combined with 2 micrograms of clavulanic acid or 2 micrograms of tazobactam per ml were 4,096, 2,048, and 1,024 micrograms/ml, respectively. The strain was susceptible to cephalosporins, aztreonam, moxalactam, and imipenem. The enzyme was purified to homogeneity, and values of the kinetic parameters Kcat, Km, and Kcat/Km were determined for different substrates. This enzyme, with a pI of 5.2, was found to have reduced affinity for broad-spectrum penicillins and cephalosporins. The values of 50% inhibitory concentrations of clavulanic acid, sulbactam, tazobactam, and brobactam are correlated with the higher KmS for substrates. The resistance of E. coli P37 to mechanism-based inactivators results from a higher level of production of the TEM-derived enzyme due to the G-to-T substitution at position 162 (G-162-->T) in the promoter region of blaTEM and from the structural modifications resulting from the Met-69-->Leu and Arg-275-->Gln substitutions that characterize IRT-14 beta-lactamase.

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Phase 1	DK	-	-
Bacterial Infections	Phase 1	-	Leo Pharma, Inc.	-
Bacterial Infections	Phase 1	GB	-	-

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