Tuesday , 26 March 2024

NEED AND SCOPE OF DEVELOPMENT OF β –LACTUMS

ABOUT AUTHOR
Siddheshwar S.S*, Pattan S.R, Wabale N.B, Pattan J.S, Dighe S.B, Bhavar S.B, Gude R.S
Pravara Rural College of Pharmacy, Pravaranagar
Goa College of Pharmacy, Panjim, Goa
E-mail: [email protected]

ABSTRACT
Wide range of β lactums are still manufactured, dispensed and marketed. β- lactums have attracted the attention of physician and medicinal chemist for their versatile biological activitites. This review is an attempt to focus the study of β lactums with their chemical additions, classifications, molecular modifications and manipulations for their extended activities. The recent growth on β lactums are well recorded and documented in the present review.
Key words: OXA, KPC, VIM, β- lactums.
INTRODUCTION
Definition 
β -lactumases are enzymes  produced by bacteria of both gram+ve and gram –ve and are responsible for their resistance to β-lactum antibiotics like penicillins, cephamycins, and carbapenems (ertapenem) (Cephalosporins are relatively resistant to β-lactumase).These antibiotics have a common element in their molecular structure: a four-atom ring known as a β-lactum. The lactumase enzyme breaks that ring open, deactivating the molecule’s antibacterial properties. β-lactumases are enzymes produced by pathogenic bacteria to destroy β-lactum antibiotics, such as penicillins and cephalosporins. Most cases of antibiotic resistance are caused by the presence of these secretory enzymes. β -Lactumase is an enzyme comprised of short chains of amino acids. It’s most promising use is as a catalyst for the hydrolysis and aminolysis of depsipeptides. In the light of above facts it was decided to complie a review on the growth and development of new generation of β-lactums for versatile biological activities.

Penicillinase– Penicillinase is a specific type of β-lactumase, showing specificity for penicillins, again by hydrolysing the β-lactum ring. Molecular weights of the various penicillinases tend to cluster near 50 kiloDaltons.Penicillinase was the first β-lactumase to be identified: It was first isolated by Abraham and Chain in 1940 from Gram-negative E. coli even before penicillin entered clinical use, but penicillinase production quickly spread to bacteria that previously did not produce it or produced it only rarely. Penicillinase-resistant β-lactums such as methicillin were developed, but there is now widespread resistance to even these.

Class A β-lactumases are most commonly employed by bacteria to hydrolyze various β-lactums. Although they are similar to each other at levels of primary protein sequence and tertiary structure, they behave diversely with respect to substrate specificity and activity. In order to identify the regions of the polypeptide chain containing amino acid residues that determine the specific behavior of class A enzymes, novel hybrid β-lactumase genes were previously created by Leung et al. (Protein Eng. 6, pp.66 Suppl.) using in vivo intramolecular homologous recombination.

These hybrid genes have their N-terminal and C-terminal coding moieties derived respectively from the β-lactumase I (PenPC) gene of Bacillus cereus and the Bacillus licheniformis β-lactumase (PenP) gene. In this present study, five of these genes were selected for detailed analysis. The enzymes were over-expressed in an efficient Bacillus subtilis expression and secretion system and purified from the culture supernatant. The five hybrid β-lactumase enzymes studied in this project are named as Hyb 8(C²⁸³L¹²), Hyb 7 (C²⁴⁶L⁴⁹), Hyb 5 (C²¹²L⁸³), Hyb 12 (C²⁰⁰L⁹⁵) and Hyb 6 (C³⁷L²⁵⁸). For example, C³⁷L²⁵⁸ indicates that out of the 295 amino acids, the first 37 are derived from β-lactumase I of B. cereus, the next 258 (residue 38-295) from the β-lactumase of B. licheniformis. According to the enzyme activity studies using penicillin G and penicillin V as substrates, the seven enzymes can be divided into two groups:
Group 1 contains the wild-type β-lactumase I (PenPC), Hyb 8, Hyb 7, Hyb 5 and Hyb 12;
Group 2 includes the wild-type B. licheniformis enzyme (PenP) and Hyb 6.
GROUP 2a: Penicillinase, Molecular Class. The2a subgroup contains just penicillinases.
GROUP 2b: Broad-Spectrum, Molecular Class A.2b Opposite to 2a, 2b are broad-spectrum β-lactumases, meaning that they are capable of inactivating penicillins and cephalosporins at the same rate.
Furthermore, new subgroups were segregated from sub group 2b: Classification of β- Lactumase, Functional Classification
Group 1
CEPHALOSPORINASE, Molecular Class C (not inhibited by clavulanic acid).Group 1 are cephalosporinases not inhibited by clavulanic acid, belonging to the molecular class C
Group 2
Group 2 are penicillinases, cephalosporinases, or both inhibited by clavulanic acid, corresponding to the molecular classes A and D reflecting the original TEM and SHV genes. However, because of the increasing number of TEM- and SHV-derived β-lactumases, they were divided into two subclasses, 2a and 2b.
2.1. GROUP 2be: EXTENDED-SPECTRUM, Molecular Class A. Subgroup 2be, with the letter “e” for extended spectrum of activity, represents the ESBLs, which are capable of inactivating third-generation cephalosporins (ceftazidime, cefotaxime, and cefpodoxime) as well as monobactams (aztreonam).
2.2. GROUP 2br: INHIBITOR-RESISTANT, Molecular Class A (diminished inhibition by clavulanic acid).The 2br enzymes, with the letter “r” denoting reduced binding to clavulanic acid and sulbactam, are also called inhibitor-resistant TEM-derivative enzymes; nevertheless, they are commonly still susceptible to tazobactam, except where an amino acid replacement exists at position met69.
GROUP 2c: CARBENICILLINASE, Molecular Class A.Latersubgroup 2c was segregated from group 2 because these enzymes inactivate carbenicillin more than benzylpenicillin, with some effect on cloxacillin.
GROUP 2d:CLOXACILANASE, Molecular Class D or A.Subgroup 2d enzymes inactivate cloxacillin more than benzylpenicillin, with some activity against carbenicillin; these enzymes are poorly inhibited by clavulanic acid, and some of them are ESBLs.the correct term is “OXACILLINASE”. These enzymes are able to inactivate the oxazolylpenicillins like oxacillin, cloxacillin, dicloxacillin. The enzymes belong to the molecular class D not molecular class A.
GROUP 2e: Cephalosporinase, Molecular Class A.Subgroup 2e enzymes are cephalosporinases that can also hydrolyse monobactams, and they are inhibited by clavulanic acid
GROUP 2f: Carbapenamase, Molecular Class A.Subgroup 2f was added because these are serine-based carbapenemases, in contrast to the zinc-based carbapenemases included in group 3
Group 3
Metalloenzyme, Molecular Class B (not inhibited by clavulanic acid).Group 3 are the zinc-based or metallo {β}-lactumases, corresponding to the molecular class B, which are the only enzymes acting by the metal ion zinc. Metallo B-lactumases is able to hydrolyse penicillins, cephalosporins, and carbapenems. Thus, carbapenems are inhibited by both group 2f (serine-based mechanism) and group 3 (zinc-based mechanism)
Group 4
Penicillinase, No Molecular Class (not inhibited by clavulanic acid).Group 4 are penicillinases that are not inhibited by clavulanic acid, and they do not yet have a corresponding molecular class.

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