Resistance-causing enzymes inhibitors

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). 

However, I5g measurements do not provide information about the biochemical characteristics of the enzyme-inhibitor interaction and what specific feature of the interaction may have changed and so caused the resistance. Also, I5g measurements need to be done with pooled tissues of several to many insects, depending on their size. To study the frequency of the resistant target site in a population, measurements must be done in individual insects. This can and has been done in house flies (58. 6J.), an armyworm (59), and plant hoppers and leaf hoppers (62.). Detailed inhibition kinetics studies will reveal if a mutation has occurred (58). A mutation causing the enzyme to have decreased affinity for the inhibitor is most clearly reflected in Kinverse relationship between and kj, kj is smaller in resistant insects with insensitive AChE. This is illustrated in Table 2. 

ENR from M.tuberculosis is the target site for tuberculosis treatment by the drug isoniazid. Unfortunately resistance to this treatment is building up in the causative agent. A way forward would be to design new inhibitors based on the information derived from structural studies on the enzyme inhibitor complex. 

Red blood cells also contain sufficient acid phenylphospha-tase for mild hemolysis to cause false elevations. Therefore, inhibitors such as ethanol, formaldehyde, copper sulfate> and 1-tartrate have been used to inhibit selectively the enzyme of one or more tissues and enhance the specificity of the test (101). Ethanol is unsuitable because it inhibits the enzyme from erythrocytes and prostate simultaneously, and because it yields serum activities which correlate poorly with prostatic disease. Formaldehyde inhibits the erythrocytic enzyme and has been said to yield clinically satisfactory results. The copoper resistant acid phosphatase of serum is elevated by metastatic carcinoma of the breast, as well as by other metastatic cancers, and is also elevated by a wide variety of non-cancerous diseases. 

There is evidence that protease inhibitors selectively regulate the activity of specific digestive enzymes at the level of gene expression (Rosewicz et al., 1989). Specifically, soybean trypsin inhibitor increases secretion of proteases, including a form of trypsin that is resistant to inhibition but does not cause an increase in amylase secretion. Although the relationships between protease inhibitors and exocrine pancreatic secretion have received the most attention, pancreatic secretion is increased when potato fiber is added to the diet (Jacob et al., 2000), although the mechanism and signaling pathway have not been elucidated. 

Inhibition of synthesis of the aromatic matrix by inhibitors of phenylalanine ammonia lyase causes the inhibition of deposition of aliphatic components and prevents development of diffusion resistance. Inhibition of synthesis of peroxidase, the enzyme involved in the deposition of the polymeric phenolic matrix, caused by iron deficiency, prevents deposition of aliphatic components of suberin. 

Enalapril maleate is an orally active angiotensin converting enzyme (ACE) inhibitor, it lowers peripheral vascular resistance without causing an increase in heart rate. The maleate salt (enalapril) allows better absorption after oral administration. It is an ideal drug for hypertensive patients who are intolerant to beta-blocker therapy. It also shows promise in the treatment of congestive heart failure. Following oral adminishation, enalapril is rapidly absorbed and hydrolysed to... 

Correct answer = A. Methotrexate interferes with folate metabolism by acting as a competitive inhibitor of the enzyme dihydrofolate reductase. This starves cells for tetrahydrofolate, and makes them unable to synthesize purines and dTMP This is especially toxic to rapidly-growing cancer cells. Overproduction of dihydrofolate reductase, usually caused by amplification of its gene, can overcome the inhibition of the enzyme at the methotrexate concentrations used for chemotherapy, and can result in resistance of the tumor to treatment by this drug. 

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