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Revised Ambler classification of -lactamases

Article  in  Journal of Antimicrobial Chemotherapy · July 2005

DOI: 10.1093/jac/dki130 · Source: PubMed

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Journal of Antimicrobial Chemotherapy
doi:10.1093/jac/dki130
Advance Access publication 4 May 2005
Revised Ambler classification of b-lactamases
Barry G. Hall1* and Miriam Barlow2
1
Biology Department, University of Rochester, Rochester,
NY, USA; 2Department of Epidemiology, Rollins School of
Public Health, Emory University, Atlanta, GA, USA
Keywords: b-lactamases, classification, Ambler
*Corresponding author. E-mail: drbh@mail.rochester.edu
Sir,
b-Lactamases are the primary cause of bacterial resistance to
b-lactam antibiotics. The most widely used classification of
b-lactamases is the Ambler classification1 that divides b-
lactamases into four classes (A, B, C and D) based upon their
amino acid sequences. Ambler originally specified two classes:
class A, the active-site serine b-lactamases; and class B, the
metallo-b-lactamases that require a bivalent metal ion, usually
Zn2þ, for activity. Later a new class of serine b-lactamases was
found that bore little sequence similarity to the then-known class
A enzymes. Designated class C,2 its members are also known as
the ‘AmpC’ b-lactamases. Another class of serine b-lactamases,
familiarly known as the OXA b-lactamases, was found to bear
little resemblance to either class A or class C and was desig-
nated class D.3 The three classes of serine b-lactamases are suffi-
ciently different that alignment programs such as BLAST4 find
no detectable sequence similarity,5 yet there is sufficient struc-
tural similarity among the three classes of serine b-lactamases
that it is clear that they are homologous, i.e. descended from a
common ancestor.
A similar situation exists for the metallo-b-lactamases, which
are a group of enzymes with evolutionary origins that are inde-
pendent of the progenitor of the serine b-lactamases. They
hydrolyse b-lactams through an enzymic process that is dis-
tinctly different from that of the serine b-lactamases, and they
are structurally unrelated to the serine b-lactamases. It is there-
fore appropriate that the metallo-b-lactamases should be grouped
separately from the serine b-lactamases, and they are. All
metallo-b-lactamases have been defined as class B b-lactamases.
While this nomenclature accurately distinguishes the metallo-b-
lactamases from the serine b-lactamases, it inaccurately implies
that all of the metallo-b-lactamases are closely related to one
another. This implication is inappropriate because not all
metallo-b-lactamases are as closely related as their current
grouping reflects. Within class B are enzymes that are alignable
neither by DNA nor by protein sequence. Those well acquainted
with the metallo-b-lactamases are aware of the differences that
exist among the metallo-b-lactamases and have dealt with these
differences by subdividing the class B group into three
subgroups, B1, B2 and B3.6 However, in subdividing the class B
in this manner, it is implied that all subgroupings of the class B
1050
q The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights
reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org; all rights reserved.
JAC
enzymes are equal, and this is not the case. Members of sub-
groups B1 and B2 share sufficient sequence similarity that they
are legitimate sequence-based homologues, but they share insuf-
ficient similarity with members of subgroup B3 to be legitimate
sequence homologues of subgroup B3.7
The current nomenclature presents two immediate problems.
The actual amount of diversity that exists among the metallo-
b-lactamases is under-represented and is therefore scientifically
misleading.
Because the metallo-b-lactamases are all contained in one
group, it is implied that they can be treated as a cohesive
group in sequence alignments and phylogenetic analysis.
Alternately, if the subdivisions of class B are considered,
then it is implied that each subclass should be treated as an
equally separate group. Neither of these implications is cor-
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rect (Figure 1).
Classification systems are inherently stable entities because
changing systems inevitably introduces a period of some con-
fusion. However, it is understood that classification schemes
need to be updated as science increases our understanding of
what we are defining. We do not suggest abandoning the
Ambler classification system, but we do suggest that its utility
could be improved through suitable modification. Because the
b-lactamase classification system affects a wide group of
investigators in a number of disciplines, any modification
should be the subject of thoughtful discussion within the entire
b-lactamase community and should be implemented on the
basis of a consensus. As a starting point for discussion, we
suggest that one alternative would be to designate two major
groups: S, the serine b-lactamases; and M, the metallo-b-lacta-
mases. Within those would be the classes SA, SC and SD,
corresponding to the present classes A, C and D; and classes
MB and ME, corresponding, respectively to the present class
B subgroups B1 þ B2, and class B subgroup B3. It would
remain entirely legitimate to speak of MB1 and MB2, the two
major subgroups corresponding to classes B1 and B2. That
classification would facilitate addition of any newly discovered
groups within either the serine or metallo-b-lactamases, and
would if desired, permit the easy recognition of any major
clades (subgroups) within any class.
Whatever renaming is agreed upon, we emphasize that for
scientific clarity, it is important that class B1 and B2 be
given an Ambler grouping that is distinctly different from
that of the current class B3. While it may be argued that
such a renaming will make little difference, it is better to
correct a misleading classification system while it is easiest
to do so.
References
1. Ambler RP. The structure of b-lactamases. Philos Trans R Soc
Lond B Biol Sci 1980; 289: 321–31.
2. Jaurin B, Grundstrom T. ampC cephalosporinase of
Escherichia coli K-12 has a different evolutionary origin from that of
 Correspondence

Current Ambler classification and implied relationships

Hydrolyse β-lactam bond

β-lactamases in structurally related antibiotics

Class A Class B Class C Class D No consistent relationship

(serine) (metallo) (serine) (serine)

subclass B1 subclass B2 subclass B3

No consistent relationship

Current Ambler scheme and actual relationships

Hydrolyse β-lactam bond

in structurally related antibiotics
β-lactamases

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(serine) Class B No homology, hydrolyse by
(metallo) different machanisms

Class A Class C Class D unnamed subclass B3

Structural homology,
no sequence homology

Sequence homology
subclass B1 subclass B2

Figure 1. Schematic diagram of Ambler classification system.

b-lactamases of the penicillinase type. Proc Natl Acad Sci USA 1981; Journal of Antimicrobial Chemotherapy
78: 4897–901. doi:10.1093/jac/dki155
3. Ouellette M, Bissonnette L, Roy PH. Precise insertion
Advance Access publication 10 May 2005
of antibiotic resistance determinants into Tn21-like transposons:
nucleotide sequence of the OXA-1 b-lactamase gene. Proc Natl Acad
Sci USA 1987; 84: 7378– 82. Is it necessary to change the classification of
4. Altschul SF, Madden TL, Schäffer AA et al. Gapped BLAST and b-lactamases?
PSI-BLAST: a new generation of protein database search programs.
Nucleic Acids Res 1997; 25: 3389–402. Jean-Marie Frère1* and Moreno Galleni1Karen Bush2,
5. Hall BG, Barlow M. Structure-based phylogenies of the serine Otto Dideberg3,
b-lactamases. J Mol Evol 2003; 57: 255– 60.
6. Galleni M, Lamotte-Brasseur J, Rossolini GM et al. Standard 1
numbering scheme for class B b-lactamases. Antimicrob Agents
Centre d’Ingénierie des Protéines, Université de Liège,
Chemother 2001; 45: 660 –3. Belgium; 2Johnson & Johnson Pharmaceutical Research &
7. Hall BG, Salipante SJ, Barlow M. The metallo-b-lactamases Development, LLC, Raritan, NJ 08869, USA; 3Institut de
fall into two distinct phylogenetic groups. J Mol Evol 2003; 57: Biologie Structurale Jean-Pierre Ebel (CNRS-CEA-UJF),
249– 54. F-38027 Grenoble, France

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