By Paul M. Selzer
Addressing parasitic ailments and people because of micro organism, this a lot wanted reference and guide presents a different perception into the strategy followed by way of advertisement technology in the direction of infectious ailments, together with the paintings of medicinal chemists. the various authors are scientists with hands-on event of drug discovery devices in the pharmaceutical undefined. moreover, the textual content covers efforts in the direction of drug improvement in infectious illnesses from educational teams and non revenue agencies
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Additional info for Antiparasitic and antibacterial drug discovery: from molecular targets to drug candidates
Using the same gene array with RNA from methotrexate-resistant cells, increased expressions of the target (dihydrofolate reductase) and pteridine reductase and S-adenosylmethionine synthase were found . Using a diﬀerent mini-array containing all Leishmania genes encoding ABC proteins, three were found to be overexpressed in antimony-resistant cells . Microarrays and Sequencing Candidate approaches are, of course, not useful for the discovery of novel modes of drug action or resistance. Genome-wide microarrays are therefore a considerable improvement – although the genes discovered have not always been novel.
In both cases, activation results in a highly reactive and toxic free radical. Metronidazole is used to treat the anaerobes Trichomonas and Giardia and is activated by reduced ferredoxin . Prior knowledge that nitroheterocyclic compounds are prodrugs, which need to be activated, led to the identiﬁcation of a candidate enzyme, the mitochondrial type 1 nitroreductase (NTR) in T. brucei and T. cruzi. Reduced expression of NTR leads to resistance against nifurtimox and benznidazole . Classical Genetics and Genomics One very successful method to identify the targets of a novel drug is to generate pathogens that are resistant to the drug.
It is, however, often very diﬃcult to distinguish speciﬁc alterations from the background of nonspeciﬁc eﬀects that reﬂect growth inhibition or general metabolic disruption. Changes in oxidative stress-related molecules and lipids are a recurring theme. For example, the metabolomes of three genetically rather similar L. donovani strains with diﬀerent levels of antimonial resistance  were studied in diﬀerent growth and drug pressure conditions . The results were rather inconclusive, although resistance appeared to be related to better protection against oxidative stress and higher membrane ﬂuidity .