Multiple drug resistance

Infectious patients present a difficult challenge when trying to protect health care workers. These patients must be isolated from the health care workers as well as from the other patients in the hospital. Special isolation rooms are used for this purpose. These rooms are generally used for isolation of infectious tuberculosis (TB) patients, but could be used for patients with other airborne-transmitted diseases. In the United States, there were 22 812 new cases of tuberculosis in 1993, equal to 8.7 per 100 000 population. This represents a 2.8% increase since 1985, following a 6-7% annual decline from 1981-1984.Several studies have documented higher than expected tuberculin skin test (TST) conversion rates in hospital personnel.The National Institute for Occupational Safety and Health " reports that multiple-drug-resistant (MDR) strains of TB have been reported in 40 states and have caused outbreaks in at least 21 hospitals, with 18-35% of exposed workers having documented TST conversions. 

Acquired resistance has been observed by constitutive upregulation of mdr efflux pump expression due to a mutation inactivating a respective repressor or inducibly, caused by molecules transiently inactivating repressor molecules upon binding. Depending upon the substrate spectra of the respective subset of efflux pumps upregulated, a multiple drug resistance (mdr) phenotype is expressed, which in combination with a specific resistance mechanism can contribute to a clinically relevant level of resistance. 

There has, unfortunately, been a global resurgenee of tuberculosis in recent years. Multiple drug-resistant M tuberculosis (MDRTB) strains have been isolated in which resistance has been aequired to many drugs used in the treatment of this disease. 

Chloride channels themselves may directly export drugs, particularly since certain chloride channels appear to act in the same manner as P-glycoprotein (multiple drug resistance protein) [227], which is involved in the export of vincristine [228,229], daunomycin [228,229], gramicidin D [230], and cyclosporin... 

De Rosa, M. F., Sillence, D.,Ackerley, C. and Lingwood, C. Role of multiple drug resistance protein 1 in neutral but not acidic glycosphingolipid biosynthesis. /. Biol. Chem. 279 7867-7876, 2003. 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

E. Buxbaum. Co-operative binding sites for transported substrates in the multiple drug resistance transporter Mdrl. Eur J Biochem. 265 64—70 (1999). 

Chitnis V, Chitnis D, Patil S, Kant R (2000) Hospital effluent as a source of multiple drug-resistant bacteria. Curr Sci India 79 989-991... 

The phenomenon of multiple drug resistance has been well described. 

Dr. B. Rowe, Director of the Central Public Health Laboratory, London, participated in the July 19-20, 1984 International Symposium on Salmonella, in New Orleans. He was quoted in Food Chemical News (Aug. 6, 1984, page 17) as follows the British increase in cases of salmonellosis caused by multiple-drug-resistant forms of Sj. 

Gravitt KR, Ward NE, Fan D, Skibber JM, Levin B, O Brian CA (1994) Evidence that protein kinase C-alpha activation is a critical event in phorbol ester-induced multiple drug resistance in human colon cancer cells. Biochem Pharmacol 48 375-381... 

Smith CD, Zilfou JT (1995) Circumvention of P-glycoprotein-mediated multiple drug resistance by phosphorylation modulators is independent of protein kinases. J Biol Chem 270 28145-28152... 

Finally, some gram-negative organisms demonstrate a fourth mechanism of resistance. For example, strains of P. aeruginosa produce xenobiotic efflux pumps to eject antibiotics. Drug efflux mechanisms are associated with multiple drug resistance, including resistance to (3-lactam antibiotics. 

Davies J. and C.E. Amabile-Cuevas (2003). The Rise of Antibiotic Resistance. In C.F. Amabile-Cuevas (Ed.). Multiple Drug Resistant Bacteria. Horizon Scientific Press, Wymondham, UK, pp. 1-7. 

Design of DNA microarrays lead to significant improvement in the field of pharmacogenomics, which deals with the reasons behind individual differences in drug responses, toxicity, and multiple drug resistance and hence, aims to find correlations between therapeutic responses to drugs and the genetic profiles of patients. 

Parkhill, J. Dougan, G. James, K.D. Thomson, N.R. Pickard, D. Wain, J. et al. Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature, 413, 848-851 (1001)... 

Komura, I., and K. Izaki. 1971. Mechanism of mercuric chloride resistance in microorganisms. I. Vaporization of a mercury compound from mercuric chloride by multiple drug resistance strains of Escherichia coli. J. Biochem. (Tokyo) 70 885-893. 

Smith CD, Zilfou JT, Stratmann K, Patterson GML, Moore RE (1995) Welwitindolinone Analogues that Reverse P-Glycoprotein Mediated Multiple Drug Resistance. Mol Pharmacol 47 241... 

Zhang X, Smith CD (1996) Microtubule Effects of Welwistatin, a Cyanobacterial Indoli-none that Circumvents Multiple Drug Resistance. Mol Pharmacol 49 288... 

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