Challenges in antimicrobial drug discovery and the potential of nucleoside antibiotics

Antimicrobial resistance in hospital and community settings is growing at an alarming rate and has been attributed to such organisms as methicillin-resistant staphylococcus aureus, staphylococci with decreased susceptibility to vancomycin, vancomycin-resistant enterococci, multi-drug resistant pseudomonas spp., klebsiella spp., enterobacter spp, and acinetobacter spp., as well as Streptococcus pneumoniae with decreased susceptibility to penicillin and other antibacterials. To address the need for new therapies to combat resistant organisms, drug companies are refocusing their discovery efforts on developing novel agents with new mechanisms of action. The hope is that rapidly emerging technologies including combinatorial chemistry, high throughput screening, proteomics and microbial genomics will have a positive impact on antimicrobial drug discovery. These technologies should aid in the identification of novel drug targets and compounds with unique mechanisms of action other than those currently provided by the traditional antibiotics. Nucleosides are one class of compounds worthy of further investigation as antibacterials since some derivatives have shown moderate to good activity against specific bacterial strains. For example, 5'-peptidyl nucleoside derivatives can inhibit peptide deformylase, an enzyme essential for bacterial survival that is not vital to human cells. This review also includes a list of miscellaneous nucleosides that have been synthesized as potential antibacterials. More detailed investigations on structure, as it relates to the antimicrobial activity of the various classes of nucleosides, need to be conducted in order to maximize the potential of developing a potent nucleoside for the treatment of bacterial infections. This review begins with an introduction to terms followed by discussions regarding the general background and relevance for developing novel antimicrobial agents. Challenges facing the antimicrobial drug discovery process are discussed along with relevant drug targets. An overview of nucleoside chemistry as it relates to antimicrobial activity is presented, followed by a discussion of the evidence which supports the potential of this class of compounds to yield the novel antimicrobial therapies needed in the new millennium.