Drug resistance discovery

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

Because of the ultimate importance of vancomycin in the treatment of often fatal infections caused by multiple-resistant bacteria, extensive efforts have been directed toward the discovery of vancomycin derivatives with activity against these drug-resistant bacteria [89]. As a result of these efforts, several derivatives such as 41 (LY264826) have been found to be up to 500 times more effective than vancomycin itself. The most notable difference is the presence of another... 

The marine environment clearly holds a tremendous potential for the discovery of lead compounds for development of agents active against infectious diseases and parasites. Within the vast resource of marine flora and fauna are new chemotypes to stem the tide of drug-resistant microbes and insects. Tapping this biological reserve depends on the technology to collect, rapidly recognize, and characterize trace quantities of secondary metabolites. Recent advances in life-support systems and analytical instrumentation, notably with CCUBA, HPLC, NMR, and MS have made this possible. 

Following this line of work, we made the discoveries reported here. Before we indicate these, we note that the microarray datasets that we analyzed for tetracycline and chloroquine do not contain many differentially regulated reactions. The possibility remains that studying drug resistance mechanisms of the malaria parasites at the transcriptional level of their proteins is not reliable (Karine Le Roch, personal communication). 

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