Constitutive -lactamase

Bacteria produce chromosomady and R-plasmid (resistance factor) mediated P-lactamases. The plasmid-mediated enzymes can cross interspecific and intergeneric boundaries. This transfer of resistance via plasmid transfer between strains and even species has enhanced the problems of P-lactam antibiotic resistance. Many species previously controded by P-lactam antibiotics are now resistant. The chromosomal P-lactamases are species specific, but can be broadly classified by substrate profile, sensitivity to inhibitors, analytical isoelectric focusing, immunological studies, and molecular weight deterrnination. Individual enzymes may inactivate primarily penicillins, cephalosporins, or both, and the substrate specificity predeterrnines the antibiotic resistance of the producing strain. Some P-lactamases are produced only in the presence of the P-lactam antibiotic (inducible) and others are produced continuously (constitutive). 

P-Lactamases are enzymes that hydrolyze the P-lactam ring of P-lactamantibiotics (penicillins, cephalosporins, monobactams and carbapenems). They are the most common cause of P-lactam resistance. Most enzymes use a serine residue in the active site that attacks the P-lactam-amid carbonyl group. The covalently formed acylester is then hydrolyzed to reactivate the P-lacta-mase and liberates the inactivated antibiotic. Metallo P-lactamases use Zn(II) bound water for hydrolysis of the P-lactam bond. P-Lactamases constitute a heterogeneous group of enzymes with differences in molecular structures, in substrate preferences and in the genetic localizations of the encoding gene (Table 1). 

The examples discussed above constitute a selection of recent applications of the acid and basic hydrolysis of (3-lactams in synthesis. Hydrolysis and alcoholysis of (3-lactams can also be effected under roughly neutral reaction conditions when enzymes are the promoters [47]. The (3-lactamases catalyzed hydrolysis of (3-lactams is an efficient process for a broad spectrum of substrates, including those (3-lactams with base or acid sensitive groups [12-14]. This process proceeds through an acyl enzyme intermediate to give ring opened (3-amino acids. The class C (3-lactamases in particular, in Scheme 9, have the ability to catalyze the alcoholysis reaction and hence (3-amino esters are the products formed. 

This section will mainly focus on the progress made in the comprehension of /(-lactamase inhibition mechanisms , which constitutes the major actual interest to overcome the bacterial resistance issues toward /(-lactam-ring-containing antibiotics (see Section 2.03.12). /(-Lactamases, naturally produced to remedy bacterial cell wall destruction by antibiotics, efficiently hydrolyze the /(-lactam ring of penicillins into their corresponding inactive... 

Penicillins bearing an A-aminosulfcnimine (RIRZNSN=) side chain at the C-6 position constitute examples of both /3-lactamase inhibitors and dual-release prodrugs <1998JOC7600, 1999JOC3132, 2000T5699> (see also Sections 2.03.12.4 and 2.03.12.5). 

Oxidation reactions on the sulfur atom of penicillins remain the most important reactivity of S-1 encountered in the literature. Penam sulfoxides and sulfones are indeed important compounds as they confer to the skeleton an ease of thiazolidine ring opening by weakening the C(5)-S(l) and S(l)-C(2) bonds (see Section 2.03.5.9) <2004CHE816>. In particular, the former constitute key intermediates in ring-expansion transformations from penams to cephems (see Section 2.03.5.9), while the latter have a special biological interest as /3-lactamase inhibitors (e.g., sulbactam, tazobactam see Sections 2.03.1, 2.03.5.2, and 2.03.12.4). Since CHEC-II(1996) covers all the aspects of these oxidation reactions on the S-1 atom of penicillins, this section focuses on the most relevant recent papers. As there is no particular change in the subject, only a few articles have been released since 1995. 

The C-6 position of penicillins remains the most versatile one and consequently lots of examples have been reported during the last decades. The variations of the nature of the C-6 side chain fit indeed in the context of finding new broad-spectrum antibiotics <1995J(P1)1483, 2004JA8122> and potential /3-lactamase inhibitors (see Sections 2.03.5.2, 2.03.5.9, and 2.03.12.4). CHEC-II(1996) (section 1.20.5.6) <1996CHEC-II(1B)623> fully overviewed the possible transformations at C-6 and, in particular, the synthesis and reactivity of 6-diazo- and 6-halopenicillanates, which constitute key intermediates for access to various 6-substituted penicillins. Therefore, this section only intends to refresh references on that matter. 

Methylene penems constitute good /3-lactamase inhibitors as their hydrolytic metabolism leads to the formation of 1,4-thiazepines, strengthening the thus-formed acyl-enzyme complex link (see Sections 2.03.6.9 and 2.03.12.4). However, compared to penams, penem sulfones are not as good /3-lactamase inhibitors as their half-lives of hydrolysis are too short, making them labile under physiological conditions <1997BML2217>. 

Resistance to p-lactam antibiotics The inducible -lactamase The R factor mediated /3-lactamase The constitutive /3-lactamase... 

From the study of a number of these reported strains, three types of /3-lactamase have been identified (i) an inducible /3-lactamase, (ii) an R factor mediated /3-lactamase and (iii) a constitutive /8-lactamase. 

In conclusion, the majority, if not all, of the strains of Ps. aeruginosa produce an inducible -lactamase which plays an important role in the resistance of the organisms to certain penicillins and cephalosporins. In addition to this enzyme, strains of Ps. aeruginosa can also produce a further /3-lactamase which may be constitutive or R factor mediated. Unlike the inducible enzyme, these additional enzymes have the ability to hydrolyse carbenicillin. Table 7.9 shows the substrate profile of all three enzymes. The new /3-lactam antibiotics with anti pseudomonas activity... 

Class IV enzymes have a similar substrate profile to the enzymes of class III they are however resistant to inhibition by cloxacillin and sensitive to inhibition by p-chloromercuribenzoate. The most important class IV 5-lactamases are those produced by strains of Klebsiella, and are invariably constitutive and of chromosomal origin. 

Lactamases may be chromosomal or plasmid-borne, inducible or constitutive, and for this reason their terminology can be confusing. A number of classification systems have been proposed, including classes A-D based on peptide sequence. Classes A, C and D have a serine at the active site, whereas class B enzymes have four zinc atoms at their active site and these are also called metallo-(3-lactamases. Class A enzymes are highly active against ben-zylpenicillin, class B (3-lactamases are effective against penicillins and cephalosporins. Class C en-... 

Other agents with in vitro activity include rifampin, vancomycin, penicilhn, ampidllin, chloramphenicol, imipenem, clindamycin, and clarithromycin. Because of concerns of constitutive and inducible beta-lactamases in B. anthracis, peniciUin and ampidllin should not be used alone. Consultation with an infectious disease spedalist is advised... 

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