Beta-lactamase categories

Since their introduction, the effectiveness of β-lactam antibiotics has been reduced by the occurrence of bacteria that are resistant to their mode of action. Resistant Staphylococcus aureus, was reported very soon after the introduction of benzyl penicillin into clinical practice. Resistance to this class of antibiotics is most frequently due to the production of enzymes that hydrolyze the β-lactam bond in these antibiotics, thus destroying their functionality. These enzymes are β-lactamases.

Genes encoding these enzymes are variably expressed in different organisms. β-lactamases may be plasmid, transposon or chromosome mediated. Classically these enzymes are designated by three letter code and a number( Eg. TEM-1, TEM-2 OXA-1, SHV-1). The three letter abbreviations have been taken from a variety of sources like substrate of the enzymes (CARB, FUR, IMP, OXA), It's biochemical properties(SHV, NBC), names of patients from which they were isolated (TEM, ROB), names of genes (Ampc, CepA), bacteria (AER, PSE), strains (P99), hospitals (MIR, RHH), states (OHIO) and initials of authors (HMS).

Over the past years the original β-lactamases have been mutated and emerged as extended spectrum β-lactamases (ESBLs). Most of these are mutants of original TEM-1, TEM-2 and SHV-1 enzymes with 1 to 4 amino acid substitutions in the original enzymes sufficient to alter the active site. Due to this these enzymes are able to inactivate a wide number of substrates, thereby aggravating the resistance problem. Currently Lahey clinic maintains a website(http://www.lahey.org/studies/) stipulating criteria that a new sequence need to be met to qualify for a new number.

Classification

The classification and nomenclature of β-lactamases has always been riddled with problems. Several schemes have been proposed for the classification of this large family of enzymes. The first proposal was to divide β-lactamases into penicillinases that hydrolyzed penicillins and cephalosporinases that attacked cephalosprins. Subsequently, the biochemical activity and substrate profiles of different enzymes formed the basis. Later, the location of genetic determinants, whether plasmid mediated, or chromosomal became incorporated into classification schemes. Isoelectric focus point and enzyme kinetic properties were basis of further classification schemes.

These schemes all had major anomalies, but advances in molecular biology and sequence analysis studies were able to resolve most of the ambiguities of the previous studies. Based on Genbank submission data, here we are grouping these enzymes in a sequence-centered manner. The gene sequences are clustered based on the three-letter designation (Eg.TEM-1) of the sequence in the Genbank flat file. We provide database search options based on country of origin, Year of reporting, the major category to which the sequence belongs (Eg. TEM, SHV, OXA etc..) and host organism. This would enable user to gather a quick information regarding the number of occurrences of a particular type of β-lactamase.

Vancomycin categories

Vancomycin is a very successful glycopeptide antibiotic, attacking the D-alanyl-D-alanine component of the cell wall. By binding to the D-alanyl-D-alanine component, Vancomycin was able to interrupt the normal cell wall formation. However, recently bacteria have achieved resistance to vancomycin.

Vancomycin resistance is achieved by a complicated series of genes. First two of the genes are VanR and VanS. The gene products detect the presence of Vancomycin in the cell. Once detected, they direct the cell to code for the transcription of VanH, VanA, and VanX. These genes code for three corresponding enzymes: VanH, VanA, and VanX. (Some bacterial cells do not have the gene VanA. Rather, they contain the gene VanB that codes for the enzyme VanB, but the two enzymes, VanB and VanA, perform the same function; they are homologs. Sometimes these two genes are referred to in combination as VanA/B.) The three enzymes VanH, VanA, and VanX perform three specific functions in the cell. VanH is referred to as a reductase and supplies the cell with D-lactate by converting the precursor, pyruvate, in the cell. VanA joins the D-lactate with D-alanyl to produce the ester D-alanyl-D-lactate, instead of the usual D-alanyl-D-alanine. Since other enzymes are still producing the D-alanyl-D-alanine, VanX enzyme hydrolyzes the D-alanyl-D-alanine before it can be incorporated into the cell wall. This splits the ester back into its components of D-alanyl and D-alanine.

Since Vancomycin binds to the D-alanyl-D-alanine component of the cell wall it is inactive in a cell with D-alanyl-D-lactate component cell walls because it can not bind to them. Vancomycin uses hydrogen bonding to bond with the D-alanyl-D-alanine component; however, the D-alanyl-D-lactate component has a 1000-fold decrease in the hydrogen bonding capabilities. Many different bacterial cells have acquired this package of genes from Enterococcus faecium to Lactobacillus. There are also some variations on this resistance. Some bacteria like Enterococcus gallinarum use a D-serine-D-alanine component instead of D-alanyl-D-lactate. The genes responsible for Vancomycin resistance is generally designated as "van" followed by a letter. Mostly they exist as a cluster and hence in ARGO this gene category is designated as "van"

Tetracycline categories

Tetracyclines (tetracycline, doxycycline, minocycline, oxtetracycline, etc) are antibiotics which inhibit the bacterial growth by inhibitting protein synthesis. Tetracyline resistance determinants are deginated as "tet" followed by a single letter (A-Z) or "otr" (for oxytetracycline resistance followed by respctive single letter(A-C)