Challenges of antibacterial discovery

Abstract

The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

FIG. 1.

Illustration of the “discovery void.” Dates indicated are those of reported initial discovery or patent.

FIG. 2.

Antibacterial inhibitors of the cytoplasmic Mur pathway. Inhibited enzymes are indicated. Compounds are described in the text.

FIG. 3.

Single-target inhibitors. Inhibited enzymes are indicated. Compounds are described in the text.

FIG. 4.

Single-target inhibitors that have reached the clinic (and their relations). (A) Actinonin; (B) BB83698; (C) LBM415; (D) triclosan; (E) GSK FabI inhibitor; (F) AFN-1252; (G) CG400549; (H) MUT37307; (I) iclaprim; (J) trimethoprim.

FIG. 5.

Multitargeted compounds. Compounds are described in the text. (A to F) Dual inhibitors of DNA gyrase and topoisomerase II. (G) Inhibitor of DNA Pol IIIC and -E of Gram-positive organisms. (H and I) Inhibitors of β-keto-acyl-ATP synthases of FAS II. (J) Nitazoxanide, an inhibitor that inactivates a cofactor, thiamine triphosphate, of the enzyme pyruvate:ferredoxin oxidoreductases.

FIG. 6.

Spectra and target locations of antibacterials. Drugs in red are active against Gram-positive organisms only and have cytoplasmic targets. Drugs in black are broad-spectrum cytoplasmic agents. Drugs in blue act extracellularly. Only 4 classes are currently useful against P. aeruginosa, with 2 acting outside the CM (polymyxin B and the β-lactams) and 2 being cytoplasmic (aminoglycosides and the FQs).

FIG. 7.

Binning of antibacterials. (A) Binning by spectrum. (B) Binning by target location. The “extracytoplasmic and transported” set includes 70 compounds from 7 classes: β-lactams, glycopeptides, daptomycin, polymyxin B, gramicidin, fosfomycin, and the aminoglycosides. Cytoplasmic compounds comprise 77 compounds from 14 classes: FQs, tetracyclines, sulfonamides, macrolides, streptogramins, trimethoprims, rifamycins, lincosamides, oxazolidinones, mupirocin, fusidic acid, novobiocin, triclosan, and chloramphenicol. The set of other drugs includes 4,623 nonantibacterials. (Adapted from reference with permission of the publisher. Copyright 2008 American Chemical Society.)

FIG. 8.

Compounds that passively diffuse into the Gram-negative cytoplasm. (A) Tetracycline; (B) trimethoprim; (C) ciprofloxacin; (D) nitrofurantoin; (E) metronidazole; (F) chloramphenicol; (G) L-161,240 (inhibitor of LpxC); (H) sulfamethoxazole; (I) ABX (inhibitor of LeuRS).