Target-Based Antimicrobial Drug Discovery

Wyeth Research, Pearl River, NY, USA.
Methods in Molecular Biology (Impact Factor: 1.29). 02/2008; 431:271-83. DOI: 10.1007/978-1-60327-032-8_21
Source: PubMed


The continued increase in antibiotic resistance among bacterial pathogens, coupled with a decrease in infectious disease research among pharmaceutical companies, has escalated the need for novel and effective antibacterial chemotherapies. While current agents have emerged almost exclusively from whole-cell screening of natural products and small molecules that cause microbial death, recent advances in target identification and assay development have resulted in a flood of target-driven drug discovery methods. Whether genome-based methodologies will yield new classes of agents that conventional methods have been unable to is yet to be seen. At the end of the day, perhaps a synergy between old and new approaches will harvest the next generation of antibacterial treatments.

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    • "The growing number of available genome sequences of human pathogen allows, for the first time, the rational prioritization of all potential drug targets for a wide range of emerging and neglected infectious diseases. The first generation of genome-based drug discovery projects have had relatively little success, to date, especially in the field of anti-bacterials [8,16]. The major drawback of earlier approaches was that despite significant upfront investment in understanding the basic biology and target validation, to build confidence-in-rationale in the molecular target, there is a high risk that drug screening efforts will yield very little. "
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    ABSTRACT: Pandemic, epidemic and endemic infectious diseases are united by a common problem: how do we rapidly and cost-effectively identify potential pharmacological interventions to treat infections? Given the large number of emerging and neglected infectious diseases and the fact that they disproportionately afflict the poorest members of the global society, new ways of thinking are required to developed high productivity discovery systems that can be applied to a larger number of pathogens. The growing availability of parasite genome data provides the basis for developing methods to prioritize, a priori, the potential drug target and pharmacological landscape of an infectious disease. Thus the overall objective of infectious disease informatics is to enable the rapid generation of plausible, novel medical hypotheses of testable pharmacological experiments, by uncovering undiscovered relationships in the wealth of biomedical literature and databases that were collected for other purposes. In particular our goal is to identify potential drug targets present in a pathogen genome and prioritize which pharmacological experiments are most likely to discover drug-like lead compounds rapidly against a pathogen (i.e. which specific compounds and drug targets should be screened, in which assays and where they can be sourced). An integral part of the challenge is the development and integration of methods to predict druggability, essentiality, synthetic lethality and polypharmacology in pathogen genomes, while simultaneously integrating the inevitable issues of chemical tractability and the potential for acquired drug resistance from the start.
    Full-text · Article · Mar 2011 · Current topics in medicinal chemistry
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    • "High-throughput screening (HTS) of synthetic chemical libraries is also regarded as an alternative to bioactive discovery and the development of combinatorial chemistry has allowed for smaller, more drug-like libraries to be screened against defined macromolecular targets. Furthermore, an increase in the availability of genomic data has provided more potential targets for these screens [142,152–157]. However, the first libraries of chemically synthesised compounds provided more quantity than quality; some produced more than million compounds, but were a disappointment, as they yielded very low numbers of, or no, active compounds [142,158]. "
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    ABSTRACT: While the oceans cover more than 70% of the Earth's surface, marine derived microbial natural products have been largely unexplored. The marine environment is a habitat for many unique microorganisms, which produce biologically active compounds ("bioactives") to adapt to particular environmental conditions. For example, marine surface associated microorganisms have proven to be a rich source for novel bioactives because of the necessity to evolve allelochemicals capable of protecting the producer from the fierce competition that exists between microorganisms on the surfaces of marine eukaryotes. Chemically driven interactions are also important for the establishment of cross-relationships between microbes and their eukaryotic hosts, in which organisms producing antimicrobial compounds ("antimicrobials"), may protect the host surface against over colonisation in return for a nutrient rich environment. As is the case for bioactive discovery in general, progress in the detection and characterization of marine microbial bioactives has been limited by a number of obstacles, such as unsuitable culture conditions, laborious purification processes, and a lack of de-replication. However many of these limitations are now being overcome due to improved microbial cultivation techniques, microbial (meta-) genomic analysis and novel sensitive analytical tools for structural elucidation. Here we discuss how these technical advances, together with a better understanding of microbial and chemical ecology, will inevitably translate into an increase in the discovery and development of novel drugs from marine microbial sources in the future.
    Full-text · Article · Mar 2010 · Marine Drugs
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