Multiple-drug resistance MDR

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. 

Whereas some transporters located in the apical wall of the enterocyte facilitate absorption, there are others that serve as efflux transporters. These are considered as the multiple drug resistance (MDR) transporters, and they play a major role in the disposition of many drugs. The most extensively studied MDR transporter is the apical P-glycoprotein (P-gp) efflux pump that reduces the fraction of drug absorbed by transporting the drug from the enterocyte back to the intestinal lumen [6]. 

Workers at Ontogen [82,83] reported the use of the OntoBLOCK system which utilizes a Tecan robot. They have implemented this technology for solid-phase synthesis to generate over 50 000 compounds corresponding to libraries of pyrroles, phosphonates, phosphinates, lactams, imidazoles, hydantoin imides and thioimides, oxazoles, and b-lac-tams. These libraries have resulted in potent and selective inhibitors of iNOS, PTPases and cdc25 phosphatase and compounds that reverse the P-glycoprotein (Pgp)-based multiple drug resistance (MDR) phenomenon in cellular assays and in animal models [98],... 

Welwitindolinone A Isonitrile 3 is the first of a family of oxindole natural products isolated from the cyanobacteria Hapalosiphon welwischii and Westiella intricate on the basis of their activity for reversing multiple drug resistance (MDR). A key transformation in the total synthesis of 3 reported (J. Am. Chem. Soc. 2008,130, 2087) by John L. Wood, now at Colorado State University, was the chlorination of 1, that in one step established both the axial secondary chloro substituent and the flanking chiral quaternary center. 

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