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

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mycobacterium tuberculosis is the causative agent of tuberculosis, a lethal infection disease that attacks the lungs. Now it becomes the major global health risk because of very long latent period, the persistent increase of new cases, and the emergence of multidrug-resistant and extensively drug-resistant strains. Therefore, there is an urgent need for the development of new, safe and more efficient tuberculosis drugs. The shikimate pathway has been considered as the attractive drug target due to its essentiality in algae, higher plants, bacteria, and fungi, but absence from mammals. In this review, we focus on the recent development of a wide variety of inhibitors of type II Mycobacterium tuberculosis dehydroquinate dehydratase, the third enzyme of this pathway. The structural and mechanistic features of the enzyme for the design and discovery of the inhibitors have been described. The key factors on the structure, binding, and affinity of the inhibitors have been also highlighted. This may direct the further development of type II Mycobacterium tuberculosis dehydroquinate dehydratase inhibitors as potent tuberculosis drugs.
    Current topics in medicinal chemistry 11/2013; DOI:10.2174/1568026613666131113150257 · 3.45 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    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.
    Marine Drugs 03/2010; 8(3):438-59. DOI:10.3390/md8030438 · 3.51 Impact Factor