P-Lactam inhibitors

In 2002, the condensation of the titanium enolate derived from 2-pyridylthio acetoxyacetate with /V-4-methoxvphenvlimine of (S)-0,0-cyclohexylidene protected glyceraldehyde has been reported to give (35.4/C4 A)-p-lactam as a single product in 65% isolated yield (Scheme 52), [137]. A reactions sequence at C-3 and C-4 led in good yield to the p-lactam inhibitor of the serine protease prostate-specific antigen. 

Bacterial signal peptidase is an example of a known enzyme that could serve as a target for new antibacterial agents [13], Recently, a catalytically active, soluble fragment of signal peptidase from E. coli has been crystallized as a complex with a P-lactam inhibitor [69], This represents a major step in the efforts toward the rational design of inhibitors that can be readily tested for their enzyme inhibition and bacterial growth-inhibition activities. 

Hydrolases Bacterial serine protease p-Lactams (inhibitors)... 

Clavulanic acid (3) was isolated from the fermentation of the microorganism Str. clavuligerus. It is a highly potent, broad spectrum and irreversible p-lactams inhibitor with clinical applications. The (3-lactam 4, structurally related to clavulanic acid, has been isolated from Str. clavuligerus. ... 

The combination of P-lactam inhibitors with other antibiotics helps to expand the speetrum of the antibiotic to a significant extent which may be observed evidently by carrying out the in vitro studies. 

In addition to variable chemical stabiUty the carbapenems are susceptible to P-lactam cleavage by a dehydropeptidase en2yme (DHP-I) located on the bmsh borders of the kidney (53). Clinically, MK 0787 (18) is used with an inhibitor of this en2yme, cil a sta tin [78852-98-9] (MK 0791) (34), 16 26 2 5 dramatic effect not only on the urinary recovery of the drug, but also reduces any nephrotoxic potential (52) (see Enzyme... 

C QHyN O SNa, as a potentially useful P-lactamase inhibitor capable of potentiating the activity of a number of clinically important P-lactam antibiotics against resistant strains (153). 

P-lactam antibiotics, exert thek antibacterial effect by interfering with the synthesis of the bacterial cell wall. These antibiotics tend to be "kreversible" inhibitors of cell wall biosynthesis and they are usually bactericidal at concentrations close to thek bacteriostatic levels. Cephalospotins are widely used for treating bacterial infections. They are highly effective antibiotics and have low toxicity. 

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). 

One approach to combating antibiotic resistance caused by P-lactamase is to inhibit the enzyme (see Enzyme inhibition). Effective combinations of enzyme inhibitors with P-lactam antibiotics such as penicillins or cephalosporins, result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, inhibition of P-lactamases alone is not sufficient. Pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. Almost any class of P-lactam is capable of producing P-lactamase inhibitors. Several reviews have been pubUshed on P-lactamase inhibitors, detection, and properties (8—15). 

Active site directed P-lactam-derived inhibitors have a competitive component of inhibition, but once in the active site they form an acyl en2yme species which follows one or more of the pathways outlined in Figure 1. Compounds that foUow Route C and form a transiendy inhibited en2yme species and are subsequendy hydroly2ed to products have been termed inhibitory substrates or competitive substrates. Inhibitors that give irreversibly inactivated P-lactamase (Route A) are called suicide inactivators or irreversible inhibitors. The term progressive inhibitor has also been used. An excellent review has appeared on inhibitor interactions with P-lactamases (28). 

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. 

One alternative strategy is to use metabolic inhibitors. Although this approach has not been used with the P-lactams, it is worthwhile bearing in mind as a possibility. It has been used in the production of tetracyclines. 

Use antibacterial in combination with 3-lactam antibiotics, semisynthetic P-iactamase inhibitor... 

The cis P-lactams 57 are shown to act as cholesterol absorption inhibitors <96BMCL1947> and 58, an analogue of the dipeptide Phe-Gly methyl ester, is a protease inhibitor <96BMCL983>. A straightforward synthesis of proclavaminic acid 59, a biosynthetic precursor of clavulanic acid, is reported <96TA2277>. 

Angiotensin converting enzyme inhibitors, atracurium, P-lactams, heparin, iron (parenteral), losartan, and streptokinase... 

Uncomplicated exacerbation Not requiring hospitalization Less than 3 exacerbations per year No comorbid illness I I V, greater than 50% predicted No recent antibiotic therapy Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis Oral Macrolide (azithromycin, clarithromycin) Second- or third-generation cephalosporin (cefuroxime, cefpodoxime, cefdinir, cefprozil) Doxycycline Ketolide (telithromycin) P-Lactam/P-Iactamase inhibitor (amoxicillin-clavulanate) Intravenous Not recommended... 

Complicated exacerbation FEV, less than 50% predicted Comorbid cardiac disease Greater than or equal to 3 exacerbations per year Antibiotic therapy in the previous 3 months Above organisms plus drug-resistant pneumococci, P-lactamase-producing H. influenzae and M. catarrhalis, Escherichia coli, Proteus spp., Enterobacter spp., Klebsiella pneumoniae Oral P-Lactam/P-Iactamase inhibitor (amoxicil 1 i n-clavulanate) Fluoroquinolone with enhanced pneumococcal activity (levofloxacin, gemifloxacin, moxifloxacin) Intravenous P-Iactam/P-Iactamase inhibitor (ampicillin-sulbactam) Second- or third-generation cephalosporin (cefuroxime, ceftriaxone) Fluoroquinolone with enhanced pneumococcal activity (levofloxacin, moxifloxacin)... 

Treatment for septic patients with hospital-acquired, ventilator-acquired, and health care-associated pneumonia is dependent on risk factors for multi-drug resistant (MDR) organisms (Fig. 79-2). Recommended treatment for patients with no MDR risk factors are third-generation cephalosporins, fluoroquinolones, ampicillin-sulbactam, or ertapenem (see Table 79-3).35 Recommended treatment for patients with MDR risk factors are P-lactam/p-lactamase inhibitors (piperacillin-tazobactam), antipseudomonal cephalosporin, or carbapenem, plus an aminoglycoside, plus vancomycin or linezolid (see Table 79-3).35 If an aminoglycoside is undesirable, a antipseudomonal fluoroquinolone may be utilized with a P-lactam/p-lactamase inhibitor. 

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