Antifungal And Antibacterial Screens

Some of the earliest examples of molecular genetic screen design come from infectious disease research. Most of the current anti-infective agents in clinical use are fermentation products. In contrast, most other therapeutics (with the possible exception of antitumor agents) are based upon chemically synthesized compounds or mammalian hormones. Rediscovery of known antibiotics is a major issue in natural products screening because of the substantial effort required to purify and characterize each active. One indication of the magnitude of this problem is the Kitasato Institute microbial chemistry database, which lists over 16,000 distinct biologically active chemical substances that have been identified from natural products fermentations. This challenge led to the early development of a number of mechanism-based assays to identify selectively rare and novel low-toxicity antibiotics acting on selective targets. Screens have been developed to identify compounds acting on the targets of virtually all antimicrobial agents in clinical use or under clinical evaluation (Table 3), and these approaches have been discussed in a number of excellent reviews [128-134]. This section will therefore only review representative new developments in this field.

Many screens for antibacterial agents have been developed by exploiting the induction properties of antibiotic resistance genes including screens for P-lactam-like, tetracycline-like, and erythromycin-like compounds [135-137]. New screens are developed as additional regulated antibiotic resistance genes are identified. The vanA gene cluster was recently used by three groups to design screening assays for cell wall acting antibiotics [138-140]. While these assays have

Table 3 Screen Designs for Detection of Antimicrobial Agents

Reported screen

Anti-infective type

Target design(s)

Sulfonamide/trimethoprim

Quinolone

Beta-lactam

Aminoglycoside

Tetracycline

Chloramphenicol

Erythromycin/clindamycin (MLS)

Vancomycin (glycopeptide)

Polymyxin B

Bacitracin

Daptomycin

Amphotericin B (polyene) Imidazole/triazole Naftifine/tolnaftate Echinocandin Benzimidazole carbamate folate metabolism DNA gyrase bacterial cell wall biosynthesis bacterial 30S ribosome subunit bacterial 30S ribosome subunit bacterial 50S ribosome subunit bacterial 50S ribosome subunit bacterial cell wall biosynthesis bacterial cell membrane bacterial cell wall biosynthesis lipoteichoic acid biosynthesis fungal cell membrane lanosterol 14a-demethylase squalene monooxygenase ß(1 —3) glucan synthase microtubule assembly

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