BETALACTAMASES

8/4/2019 BETALACTAMASES

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-Lactamases


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Resistance Due to Destruction or

Inactivation of a Drug

- Lactam Resistance.

PBPs and Lactamases are proteins which

disrupt the Lactam bond to form an acyl-enzymecomplex.

In Lactamases, a water molecule serves as theattacking nucleophile in the deacylation step.

The major difference between Lactamases andPBPs is in the rate of deacylation.


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- Lactam Resistance. Lactamases are a heterogeneous group with

structural similarities.

Classification:

Ambler Classification. A, C, D Groups (Serine Lactamases ) B Group (Metallo- Lactamases )

Bush-Jacoby-Medeiros Classification. Classification according to functional similarities. There

are 4 Groups and many sub-groups.


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Bush-Jacoby-Medeirosclassification

Major Subgroup Ambler Classification Main Attributes

Group 1(Cephalosporinases)

C (Cephalosporinases) Chromosomal, Resistantto CA, Carbapenem Notattacked

Group 2 (Penicillinases) 2a A Staphylococcal enzyme

2b A Broad Spectrum TEM1,TEM2, SHV1

2be A ESBL

2br A Inhibitor Resistant TEM

2c A Carbenicillin hydrolyzing

2e A Cephalosporinases

Inhibited by CA

2f A CarbapenemasesInhibited by CA

2d D Cloxacillin Hydrolyzing

Group 3 3a B (Metalloenzyme) Zinc dependentCarbapenemases

3b B (Metalloenzyme)

3c B (Metalloenzyme)

Group 4 Not classified Miscellaneous Enzymes


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- Lactam Resistance.

Lactamases are chromosomal, plasmid ortransposon mediated.

They may be constitutive or inducible. They are secreted:

In the periplasmic space in Gram Negativeorganisms

and

In to the surrounding by Gram Positive organisms


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Class A - Lactamases

Two common class A (BJM Group 2) Lactamases are TEM-1 and SHV-1 found in

Enterobacteriaceae They are Penicillanases, No Cephalosporinase

activity

They are progenitors of ESBL.

ESBL mutation renders the enzyme susceptible to

inhibitors (Clav Acid, Sulbactam, Tazobactam) There are many non-TEM and non-SHV class A

ESBL


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Class A - Lactamases

There are many non-TEM and non-SHV class AESBL

Two important families are CTX-M and PER. They are close in amino acid sequence to

Cephalosporinases of K oxytocaand P vulgaris.

This class of ESBL hydrolyze CTX and CRO betterthan CAZ and Tazobactam is better inhibitor than

Clav Acid. Carbapenems are quite stable to class A -

Lactamases


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Class B - Lactamases These (BJM Group 3) are so called Metalloenzymes

as they need Zn or some other metal for theiractivity and they are inhibited by chelators.

Carbapenems and Cephamycins are hydrolyzed. Inhibitors (Clav Acid, Sulbactam, Tazobactam) are

not effective. Class B - Lactamases are subdivided in to three

subgroups B1, B2, B3. Although the genes encoding their production are

not identical, these Class B - Lactamases showvery similar structure Class B Lactamases are chromosomally

encoded and their expression may be constitutive orinducible.


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Class C - Lactamases

These (BJM Group 1) are produced by almost allGram negative bacteria.

Class C Lactamases are chromosomallyencoded and they are Cephalosporinases.

Repression and activation are closely related to cellwall synthesis. In the event of high levels of cell walldegradation products, the repressor is repressed.

Inhibitors (Clav Acid, Sulbactam, Tazobactam) arenot effective.

The encoding genes are carried on a plasmid andthey are of four types.

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BETALACTAMASES