-Lactamases

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-enzyme complex. In Lactamases, a water molecule serves as the attacking nucleophile in the deacylation step. The major difference between Lactamases and PBPs is in the rate of deacylation.

Resistance Due to Destruction or Inactivation of a Drug

- 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.

Bush-Jacoby-Medeiros classification Group 1 (Cephalosporinases) Group 2 (Penicillinases)

Major Subgroup

Ambler Classification C (Cephalosporinases)

Main Attributes Chromosomal, Resistant to CA, Carbapenem Not attacked Staphylococcal enzyme Broad Spectrum TEM1, TEM2, SHV1 ESBL Inhibitor Resistant TEM Carbenicillin hydrolyzing Cephalosporinases Inhibited by CA Carbapenemases Inhibited by CA

2a 2b 2be 2br 2c 2e 2f

A A A A A A A

2d
Group 3 3a 3b 3c Group 4

D
B (Metalloenzyme) B (Metalloenzyme) B (Metalloenzyme)

Cloxacillin Hydrolyzing
Zinc dependent Carbapenemases

Not classified

Miscellaneous Enzymes

Resistance Due to Destruction or Inactivation of a Drug

- Lactam Resistance. Lactamases are chromosomal, plasmid or transposon mediated. They may be constitutive or inducible. They are secreted:
In the periplasmic space in Gram Negative organisms and In to the surrounding by Gram Positive organisms

Resistance Due to Destruction or Inactivation of a Drug

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

Resistance Due to Destruction or Inactivation of a Drug

Class A - Lactamases There are many non-TEM and non-SHV class A ESBL Two important families are CTX-M and PER. They are close in amino acid sequence to Cephalosporinases of K oxytoca and P vulgaris. This class of ESBL hydrolyze CTX and CRO better than CAZ and Tazobactam is better inhibitor than Clav Acid. Carbapenems are quite stable to class A Lactamases

Resistance Due to Destruction or Inactivation of a Drug

Class B - Lactamases These (BJM Group 3) are so called Metalloenzymes as they need Zn or some other metal for their activity 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 show very similar structure Class B Lactamases are chromosomally encoded and their expression may be constitutive or inducible.
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Resistance Due to Destruction or Inactivation of a Drug

Class C - Lactamases These (BJM Group 1) are produced by almost all Gram negative bacteria. Class C Lactamases are chromosomally encoded and they are Cephalosporinases. Repression and activation are closely related to cell wall synthesis. In the event of high levels of cell wall degradation products, the repressor is repressed. Inhibitors (Clav Acid, Sulbactam, Tazobactam) are not effective. The encoding genes are carried on a plasmid and they are of four types.
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