Abstract
Serious attempts to address antibiotic resistance, a worldwide public health concern, have recently become more intensive. In hospital settings, resistance to antibacterial agents has been recognized by clinicians for several decades. Resistant strains are now isolated on a daily basis from patients with community-acquired infections further elevating the level of concern among public health officials. The pharmaceutical industry has generally focused its attentions on chronic therapeutic indications in recent years (e.g. cardiovascular and metabolic diseases), but will likely be forced to reengage in antibacterial discovery efforts as therapeutic options diminish for the treatment of infections caused by multidrug resistant pathogens. The ability to squeeze additional utility out of known classes of antibacterial agents has become limited and antibacterial discovery scientists will need to focus on new approaches and targets. These new approaches will need to include strategies that explicitly address resistance up front and simultaneously attempt to facilitate the slower development of resistance as new compound classes enter clinical use. One approach that can be a useful component of antibacterial discovery efforts and prospectively address resistance is structure-guided design (SGD). This review will describe several recent examples in which SGD was applied as part of a multidisciplinary effort to address antibacterial resistance. These include dihydrofolate reductase inhibitors, broad-spectrum β-lactamase inhibitors, novel oxazolidinones, aminoglycoside mimetics, peptide deformylase inhibitors, and inhibitors that simultaneously target DNA gyrase and topoisomerase IV.
Keywords: Antibiotic resistance, antibiotic drug discovery, resistance mechanisms, structure-guided design, dual targeting
Anti-Infective Agents in Medicinal Chemistry
Title: The Use of Structure-Guided Design to Discover New Anti-Microbial Agents: Focus on Antibacterial Resistance
Volume: 8 Issue: 1
Author(s): P. S. Charifson, T. H. Grossman and P. Mueller
Affiliation:
Keywords: Antibiotic resistance, antibiotic drug discovery, resistance mechanisms, structure-guided design, dual targeting
Abstract: Serious attempts to address antibiotic resistance, a worldwide public health concern, have recently become more intensive. In hospital settings, resistance to antibacterial agents has been recognized by clinicians for several decades. Resistant strains are now isolated on a daily basis from patients with community-acquired infections further elevating the level of concern among public health officials. The pharmaceutical industry has generally focused its attentions on chronic therapeutic indications in recent years (e.g. cardiovascular and metabolic diseases), but will likely be forced to reengage in antibacterial discovery efforts as therapeutic options diminish for the treatment of infections caused by multidrug resistant pathogens. The ability to squeeze additional utility out of known classes of antibacterial agents has become limited and antibacterial discovery scientists will need to focus on new approaches and targets. These new approaches will need to include strategies that explicitly address resistance up front and simultaneously attempt to facilitate the slower development of resistance as new compound classes enter clinical use. One approach that can be a useful component of antibacterial discovery efforts and prospectively address resistance is structure-guided design (SGD). This review will describe several recent examples in which SGD was applied as part of a multidisciplinary effort to address antibacterial resistance. These include dihydrofolate reductase inhibitors, broad-spectrum β-lactamase inhibitors, novel oxazolidinones, aminoglycoside mimetics, peptide deformylase inhibitors, and inhibitors that simultaneously target DNA gyrase and topoisomerase IV.
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Cite this article as:
Charifson S. P., Grossman H. T. and Mueller P., The Use of Structure-Guided Design to Discover New Anti-Microbial Agents: Focus on Antibacterial Resistance, Anti-Infective Agents in Medicinal Chemistry 2009; 8 (1) . https://dx.doi.org/10.2174/187152109787047805
DOI https://dx.doi.org/10.2174/187152109787047805 |
Print ISSN 1871-5214 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6018 |
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