Lactamases inhibition

Garbapenem P-Lactamase Inhibitors. Carbapenems are another class of natural product P-lactamase inhibitors discovered about the same time as clavulanic acid. Over forty naturally occurring carbapenems have been identified many are potent P-lactamase inhibitors. Garbapenem is the trivial name for the l-a2abicyclo[3.2.0]hept-2-ene ring system (21) shown in Table 3. The synthesis (74), biosynthesis (75), and P-lactamase inhibitory properties (13,14,66) of carbapenems have been reviewed. Carbapenems are often more potent than clavulanic acid and include type I Cephases in the spectmm of inhibition. Table 3 Hsts the available P-lactamase inhibition data. Synergy is frequendy difficult to demonstrate because the compounds are often potent antibacterials. 

Other Unusual P-Lactam Based Inhibitors. There are a number of other unusual p-lactams reported to have p-lactamase inhibition activity (191—194). In general these compounds are not very potent and are not irreversible inhibitors. Data are also very Umited. 

Figure 5.24 Electrospray mass spectrum of the tryptic peptide with a retention time of 42.12 min from CMY-2 S-lactamase inhibited by tazobactam. Reprinted from Biochim. Biophys. Acta, 1547, Bonomo, R. A., Liu, J., Chen, Y., Ng, L., Hujer, A. M. and Anderson, V. E., Inactivation of CMY-2 /1-lactamase by tazobactam initial mass spectroscopic characterization , 196-205, Copyright (2001), with permission from Elsevier Science.

Reading, C. and Cole, M. (1977) Clavulanic acid a beta-lactamase-inhibiting beta-lactam from Streptomyces clavuligerus. Antimicrobial Agents and Chemotherapy, 11, 852—857. 

The discovery of the ethylidenecarbapenems, the asparenomycins, as naturally occurring /J-lactamase inactivators in the early 1980s was another striking point in /J-lactamase inhibitor research. The substituted exomethylene function in asparenomycins is a distinctive feature of this class of compounds, which many scientists recognized could be a key factor for /J-lactamase inhibition. The exo cyclic methylene is expected to increase the acylation ability, and form an a,/J-unsaturated ester of the active site serine residue as an acyl-enzyme complex. This ester will be similar in structure to the acyl-enzymes formed from clavulanate and sulfone fragmentation, and will be quite resistant to hydrolytic deacylation. Thus, the exocyclic methylene promotes acylation by the enzyme and subsequently represses deacylation. Based on... 

R. C. Moellering, /3-Lactamase Inhibition Therapeutic Implications in infectious Diseases -An Overview , Rev. Infect. Dis. 1991, 13, S723-S726. 

Mechanistic Aspects of /8-Lactamase Inhibition The clinically important /3-lactamases, e.g., the penases, TEM(lll). and cephases(I). are serine proteases that form an acyl enzyme intermediate with /1-lactam substrates and /i-lactam-derived /3-lactamase inhibitors. Mechanistic studies using several /3-lactamase inhibitors have been extensively reviewed and a general inhibition scheme is illustrated in Figure 1. 

Modem /8-lactamasc-rcsistant cephalosporins have been reported to be inhibitors of type I Cephases. /3-Lactamase inhibition occurs through the transiently inhibited enzyme species, which requires a good C-3 leaving group. 

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... 

The introduction of a styryl group at the C-6 position of penams finds its application in the intrinsic /3-lactamase inhibition activity of 6-vinyl penicillins 26 (see Sections 2.03.5.9 and 2.03.12.4). Its incorporation can be performed via a cobaltoxime-mediated radical cross-coupling reaction between a 6-bromopenicillanate and styrene (Scheme 15) < 1996BML2289>. 

The presence of a styryl group (R1 = Ph) at C-6 confers to penicillins a /3-lactamase inhibition activity (see Section 2.03.12.4) by acidifying H-6, which provokes the C(5)-S(l) bond cleavage (see Section 2.03.5.3.2) toward the formation of l,4-thiazepin-7-ones 36 (Scheme 20) <1996BML2289>. 

I review of the chemistry of /3-lactamase inhibition. Kiwwle.s has described two classes of /3-lactamase inhibi-UHs class I inhibitors that have a heteroatom leaving group a position I (e.g.. clavulanic acid and. sulbactam) and class... 

Because of their structural similarity to the fi-lactams, the solid-phase synthesis of 3-sultams (1,2-thiazetidine-l,1-dioxides) is of relevance. However, in spite of their structural analogy to the fi-lactams, very little is known about the biological activity of P-sultams. Thus far, the P-sultams examined have shown disappointingly weak P-lactamase inhibition activity [49], although by using combinatorial technologies... 

C l I XO. demonstrate P-lactamase inhibition. Few derivatives have been reported that have substitution at C-6. The hydroxyalkyl compounds [66825-93-2] (19) and (20), C10H13NO6, have been disdosed as P-lactamase inhibitors (13) where the cis epimer (19) is more active than the trans (20). 

These antibiotics have been isolated from cultures of S. olivaceus and have been found to have P-lactamase-inhibiting as well as antibacterial properties (Brown et al., 1977 Butterworth et al., 1979). 

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