Mutant prevention concentration

Moxifloxacin s MIC90 value of 1 mg L"1 means that it has the same in vitro activity against M. tuberculosis as levofloxacin, and is more effective than ofloxacin (MIC90 = 2 mg L"1) and ciprofloxacin (MIC90 = 4 mg IT1) [192-194]. A combination of moxifloxacin and isoniazid proved to be more effective in vivo than the individual compounds [195,196], whereas a combination with ethambutol was less effective [196]. Based on the mutant prevention concentration (MPC), which is a parameter for the selection of resistant pathogens during antibiotic treatment, moxifloxacin was found to be the most effective fluoroquinolone against M. tuberculosis [197]. 

Rodriguez JC, et al. Mutant prevention concentration comparison of fluoroquinolones and linezolid with Mycobacterium tuberculosis. J. Antimicrob. Chemother., 2004, 53, 441-444. 

Sindelar G, et al. Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria. Antimicrob. Agents Chemother.,... 

Metzler K, et al. Comparison of minimal inhibitory and mutant prevention drug concentrations of 4 fluoroquinolones against clinical isolates of methi-cillin-susceptible and -resistant Staphylococcus aureus. Int. J. Antimicrob. 

Hundreds of metabohc reac tions take place simultaneously in cells. There are branched and parallel pathways, and a single biochemical may participate in sever distinct reactions. Through mass action, concentration changes caused by one reac tion may effect the kinetics and equilibrium concentrations of another. In order to prevent accumulation of too much of a biochemical, the product or an intermediate in the pathway may slow the production of an enzyme or may inhibit the ac tivation of enzymes regulating the pathway. This is termed feedback control and is shown in Fig. 24-1. More complicated examples are known where two biochemicals ac t in concert to inhibit an enzyme. As accumulation of excessive amounts of a certain biochemical may be the key to economic success, creating mutant cultures with defective metabolic controls has great value to the produc tion of a given produc t. 

Narhi et al. (1991) recently reported an enhancement in the thermal stability of aprA-subtilisin by three point mutations. The mutations were ASNi. SER and ASN. SER to prevent cyclisation with the adjacent glycines and ASN . ASP in the Ca binding loop. The mutant form also exhibits improved stability to detergent denaturation with little dependence on calcium concentration. Subtilisin 8350 (derived from subtilisin BPN via six site-specific mutations) was found to be 100 times more stable than the wild type enzyme in aqueous solution and 50 times more stable than the wild type in anhydrous dimethylformamide (Wong et al, 1990)... 

There are just a few studies of the use of caspase inhibitors to prevent apoptosis. Most studies concentrate on the expression of proteins of the IAP family (XIAP being the most noticeable) and the viral components p35 and CrmA (Vives et al., 2003a). CrmA, encoded by the smallpox virus, is a pseudo-substrate for serine and cysteine proteases. It inhibits caspases 1, 8, and 10 in several cell types (Sauerwald et al., 2003). p35 is a wide-spectrum caspase inhibitor encoded by baculoviruses, and it also behaves as a pseudo-substrate, inhibiting caspases 1, 3, 6, 7, 8, and 10 (Zhou et al., 1998). XIAP is the most potent member of the IAP family. It is found in the mammalian genome and is responsible for the inhibition of caspases 3, 7, and 9 (Sauerwald et al., 2002). An increased protective effect is found in CHO and HEK-293 cells expressing a XIAP mutant resistant to degradation (XIAP-BIR123) when compared with the wild-type protein (Sauerwald et al., 2002). 

Degradation of L-cysteine by cysteine desulfhydrase or other PLP enzymes present in the cells was successfully prevented by addition of hydroxylamine or semi-carbazide to the incubation mixture. A mutant strain of Ps. thiazolinophilum lacking cysteine desulfhydrase was isolated and used to produce L-cysteine from d,l-ATC in a molar yield of 95% and at a product concentration of 31.4 g L 1[12S. Pseudomonas desmolytica A] 3872, one of the L-cysteine producers isolated was found to lack the ability to convert d-ATC into L-cysteine it is an ATC racemase-deficient strain 129l. However, little is known about the enzymological properties and function of the racemase. 

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