oa Editorial [Hot Topic: The Need to Redefine Antimicrobial Drug Discovery (Executive Guest Editor: Eleftherios Mylonakis)]

There is a clear and emergent need for a new approach in antimicrobial drug discovery. Pathogenic microorganisms have demonstrated an impressive ability to adapt and develop resistance to antimicrobial agents. The quick emergence of resistance to essentially all broad-spectrum antimicrobial agents has been well established. For example, resistance to penicillin was observed 3 years after its deployment, while the interval was 5 years for tetracycline, 1 year for methicillin, etc. [1]. Moreover, with the possible exception of tigacycline and the narrow spectrum agents linezolid and daptomycin, fluoro-quinolones are the last class of truly broad-spectrum antimicrobial agents with activity against both Gram-positive and Gram-negative bacteria. In this issue of Current Pharmaceutical Design, we outline some of the most exciting developments on the field, with a focus on bacterial and fungal pathogens. First, a series of papers outlines the use of a number of different invertebrate models [2, 3, 4, 5]. The common hypothesis behind the approach outlined in these papers is based on the finding that most pathogens use the same virulence mechanisms when they infect mammals and invertebrates. Our group from Massachusetts General Hospital and Harvard Medical School details the use of the nematode Caenorhabditis elegans as a model host to simultaneously identify new classes of antimicrobial agents (including agents with antivirulence or immunomodulatory efficacy) as well as to evaluate toxicity and efficacy [2]. Du et al. (National University of Singapore) propose to employ the cell-free hemolymph (CFH) from horseshoe crabs as a quick and convenient tool for antimicrobial drug screening [3]. Also, the last two papers in this sub-section outline two important insect models. The paper by Vilcinskas (Justus-Liebig University of Giessen, Giessen, Germany) highlights the use of Galleria mellonella and proposes the development of the insect metalloproteinase inhibitor (IMPI) that exhibits a specific and potent activity against microbial metalloproteinases and inhibits a number of virulence factors of human pathogens [4]. Lionakis et al. summarize the experience at MD Anderson Cancer Center from the use of Drosophila melanogaster, a model host that provides a well studied immune system and powerful genetics and should be especially useful for the study of immunomodulatory compounds [5,6]. Taken together, these surrogate invertebrate hosts fill an important niche in pathogenesis research and provide us with a unique opportunity to identify novel compounds and study basic, evolutionarily conserved aspects of virulence and host response. It should be noted however that invertebrate model systems have different strengths and weaknesses and the selection of a model system dependents on the virulence factors and host responses of interest [7,8]. Findings from invertebrate models should be often validated and studied in mammalian systems. This approach is the basis for the “multi-host” pathogenesis system that is based in cross-species studies among divergent model hosts and allows the discovery of fundamental virulence and host response mechanisms that are independent of the host. An example of this approach is outlined in the paper by Zaborina et al. (University of Chicago). The authors used two widely divergent hosts (the nematode C. elegans and a murine model) to evaluate the hypothesis that the intestinal track of a critically ill host can enhance bacterial virulence. The need for this type of approach is obvious when we consider the ultimate goal of this group that is the development of new agents that can manipulate the “local microenvironment” within the intestine [9]. Importantly, murine models can also be developed further and this issue provides two examples: the intestinal track model by Zaborina et al. noted above and the model by Kerekov et al. (Bulgarian Academy of Sciences) that used severe combined immunodeficiency (SCID) mice to study protein-engineered molecules [10]. In the last sub-section, Termentzi and colleagues (University of Athens, Greece) examine a significant question in drug development: What libraries can provide the highest rate of hits? Especially the complexity and cost associated with the study of natural products and their derivatives can discourage researchers. However, this paper reminds us that “from the 109 new antibacterial drugs approved between 1981 2006, 69% originated from natural products […] while for the antifungal drugs 21% were natural derivatives or compounds mimicing natural products” [11]. Finally, Tegos and colleagues from the University of New Mexico bring everything together as they desribe the microbial multidrug efflux systems and their approaches to discover and develop efflux pump inhibitors [12], while Hamblin and co-workers from the Massachussetts General Hospital report on the drug discovery of antimicrobial photosensitizers using animal models [13]. In conclusion, we envisage that the future of drug discovery will be based on the primary screen of compound libraries in a variety of hosts and we hope that the papers in this issue will inspire researchers to explore new methods for antimicrobial drug discovery. Let's allow our imagination to take us toward novel approaches in drug discovery. These approaches could include the combination of conventional antimicrobial agents with small molecules as well as use of model hosts in the discovery and development of compounds in vivo. Importantly these new systems have the potential to result in the development of less-toxic and more effective antimicrobial agents, including drugs with immunomodulatory and antivirulence activity. The need to redefine our approach could not be more immediate.....