The challenge of multidrug resistance: actual strategies in the development of novel antibacterials

Abstract

Bacterial resistance against established antibiotics is becoming an increasingly important global healthcare problem. Despite enormous efforts, the number of therapeutically useful compounds that emerge from chemical derivatisation programs, which aim at circumventing mechanisms of resistance, is continuously decreasing and no truly novel class of compound has been introduced into therapy for nearly four decades. Hopes are now set on a thorough elucidation of bacterial cell functions to identify new bacterial target sites, and on the development of novel compounds with alternative modes of action. The pursuit of these strategies is rendered possible by employment of biotechnologically based methods such as in vivo modification of biosynthetic routes in antibiotic-producing organisms, large-scale screening assays with isolated bacterial targets, the molecular profiling of bacterial genomes and proteomes, and the development and clinical use of biochips as diagnostic tools for rapid identification and characterization of pathogenic strains. As one of the most promising class of compounds known to date with unique modes of action that escape most known mechanisms of resistance, peptic agents have recently came under the focus of anti-infective research, just as extracellular signalling molecules (autoinducer) have emerged as new bacterial target sites.

Isolation and Identification ofBacillusSpecies From Soil and Evaluation of Their Antibacterial Properties

“…Screening for new antibiotics from natural sources is becoming increasingly important for the pharmaceutical industry (18), as pathogenic bacteria are significantly becoming resistant to generally used curative agents (19).…”

Small-Molecule Inhibitor of the Shigella flexneri Master Virulence Regulator VirF

“…Thus, inhibitors that block transcription activation by VirF (preferably without detrimental effects on the growth of the bacteria) have potential to be developed into novel antimicrobial agents. The nonessential nature of VirF may reduce the probability that Shigella will develop resistance to VirF inhibitors (22,(32)(33)(34). A highthroughput screen performed by a different group identified several inhibitors of VirF activation of virB-lacZ reporter expression; however, the mechanisms of inhibition and further effects on Shigella infections were not tested (59).…”

“…Importantly, mutations that disrupt the function of AraC family virulence activators reduce bacterial virulence without affecting the growth of the bacteria (26,31). Thus, inhibition of AraC family virulence activators is expected to exert less selective pressure on bacteria to develop resistance than currently available antibiotics (22,(32)(33)(34). Multiple lines of experimental evidence indicate that targeting AraC family virulence activators can dramatically reduce the severity of infections in animal models, suggesting that AraC family proteins may be excellent targets for the development of novel antimicrobials (24)(25)(26)(27)(28).…”

Bacteria Exhibiting Antimicrobial Activities; Screening for Antibiotics and the Associated Genetic Studies

“…Screening for new antibiotics from natural sources is becoming increasingly important for the pharmaceutical industry [1] as pathogenic bacteria are quickly becoming resistant to commonly used therapeutic agents [2]. Secondary metabolites from microorganisms have a diverse chemical structure and biological activities and are produced only by some species of a genus Bacillus [3].…”