beta-lactam

ß-lactam resistance

ß-lactams belong to a family of antibiotics which is characterized by
a ß-lactam ring. Penicillins, cephalosporins, clavams (or oxapenams),
cephamycins and carbapenems are members of this family. The integrity
of the ß-lactam ring is necessary for the activity which results in
the inactivation of a set of transpeptidases that catalyze the final
cross-linking reactions of peptidoglycan synthesis.
Resistance to ß-lactams in clinical isolates is primarily due to the
hydrolysis of the antibiotic by a ß-lactamase. Mutational events
resulting in the modification of PBPs (penicillin binding proteins) or
cellular permeability can also lead to ß-lactam resistance.
ß-lactamases constitute a heterogenous group of enzymes. Several
classification schemes have been proposed according to their
hydrolytic spectrum, susceptibility to inhibitors, genetic
localisation (plasmidic or chromosomal), gene or amino-acid protein
sequence. The functional classification scheme of ß-lactamases
proposed by Bush, Jacoby and Medeiros (1995) defines four groups
according to their substrate and inhibitor profiles. Group 1 are
cephalosporinases that are not well inhibited by clavulanic acid;
group 2 penicillinases, cephalosporinases, and broad-spectrum
ß-lactamases that are generally inhibited by active site-directed
ß-lactamase inhibitors; group 3 metallo-ß-lactamases that hydrolyze
penicillins, cephalosporins, and carbapenems and that are poorly
inhibited by almost all ß-lactam-containing molecules; group 4
penicillinases that are not well inhibited by clavulanic acid.
Subgroups were also defined according to rates of hydrolysis of
carbenicillin or cloxacillin (oxacillin) by group 2 penicillinases.
The classification initially introduced by Ambler (1980) and based on
the amino-acid sequence recognizes four molecular classes designated A
to D. Classes A, C, and D gather evolutionarily distinct groups of
serine enzymes, and class B the zinc-dependent ("EDTA-inhibited")
enzymes.




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Fonzé, E., P. Charlier, Y. To'th, M. Vermeire, X. Raquet, A. Dubus,
and J-M. Frère. 1995. TEM1 beta-lactamase structure solved by
molecular replacement and refined structure of the S235A mutant. Acta
Cryst. 51:682-694.


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Commonly used B-lactam resistance markers in molecular biology
The bla gene encoding the TEM-1 ß-lactamase is the most encountered
AmpR marker used in molecular biology (pBR and pUC plasmids). TEM-1 is
a widespread plasmidic ß-lactamase that attacks narrow-spectrum
cephalosporins, cefamandole, and cefoperazone and all the
anti-gram-negative-bacterium penicillins except temocillin.
Aminothiazol chephalosporins, cephamycins, monobactams and carbapenems
are resistant to its action. It belongs to the Bush-Jacoby-Medeiros
group 2b and the molecular class A. The TEM-1 enzyme was first
reported from an E. coli isolate in 1965 and is now the commonest
ß-lactamase found in enterobacteriaceae. Resistance in more than 50%
of AmpR E. coli clinical isolates is due to TEM-1. Most
extended-spectrum ß-lactamases (ESBLs) derive from TEM-1, TEM-2 and
SHV-1 by mutations generating 1- to 4-amino-acid sequence
substitutions.


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Hot links
Amino acid sequences for TEM, SHV and OXA extended-spectrum
ß-lactamases (Link to the Lahey Clinic)

Is It Important to Identify Extended-Spectrum ß-Lactamase-Producing
Isolates? (Copyrights © by WARN Development)

Penicillin-resistant pneumococci (Copyrights © by WARN Development)

Penicillin-resistant Streptococcus pneumoniae (Link to ENARE)

Methicillin-resistant staphylococci (Link to ENARE)

Penicillin derivatives (Copyrights © by Purdue Research Foundation)

Penicillins (link to the University of Winconsin Hospital)

Cephalosporin derivatives and related compounds (Copyrights © by
Purdue Research Foundation)

Cephalosporins (link to the University of Winconsin Hospital)


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Selected reading
Bush, K., G. A. Jacoby, and A. A. Medeiros. 1995. A functional
classification scheme for ß-lactamases and its correlation to
molecular structure. Antimicrob. Agents Chemother. 39:1211-1233.
Review. No abstract available.

Bush, K., and G. Jacoby. 1997. Nomenclature of TEM ß-lactamases. J.
Antimicrob. Chemother. 39:1-3. Review. No abstract available.

Frère, J. 1995. Beta-lactamases and bacterial resistance to
antibiotics. Mol. Microbiol. 16:385-395. Review.

Ghuysen, J. M. 1991. Serine ß-lactamases and penicillin-binding
proteins. Annu. Rev. Microbiol. 45:37-67. Review. No abstract
available.

Ghuysen, J. M. 1994. Molecular structures of penicillin-binding
proteins and ß-lactamases. Trends Microbiol. 2:372-379.

Jacoby, G. A. 1994. Extrachromosomal resistance in Gram-negative
organisms: the evolution of ß-lactamase. Trends Microbiol. 2:357-360.

Livermore, D.M. 1995. ß-lactamases in laboratory and clinical
resistance. Clin. Microbiol. Rev. 8:557-584. Review.

Medeiros, A. A. 1997. Evolution and dissemination of ß-lactamases
accelerated by generations of ß-lactam antibiotics. Clin. Inf.
Diseases. 24(Suppl 1):S19-S45. Review.

Matagne, A., J. Lamotte-Brasseur, and J.M. Frère. 1998. Catalytic
properties of class A beta-lactamases: efficiency and diversity.
Biochem. J. 330:581-598.

Massova, I., and S. Mobashery. 1998. Kinship and diversification of
bacterial penicillin-binding proteins and ß-lactamases. Antimicrob.
Agents Chemother. 42:1-17. Review. No abstract available.

Thomson, C. J., and S. G. B. Amyes. 1993. Molecular epidemiology of
the plasmid encoded TEM-1 ß-lactamase in Scotland. Epidemiol. Infect.
110:117-125.

Thomson, C. J., P. M. Shanahan, and S. G. B. Amyes. 1994. TEM-1
plasmids in the community. Lancet 343:921. Letter. No abstract
available.



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