Small molecule inhibition of microbial natural product biosynthesis-an emerging antibiotic strategy

Abstract

A variety of natural products modulate critical biological processes in the microorganisms that produce them. Thus, inhibition of the corresponding natural product biosynthesis pathways represents a promising avenue to develop novel antibiotics. In this tutorial review, we describe several recent examples of designed small molecule inhibitors of microbial natural product biosynthesis and their use in evaluating this emerging antibiotic strategy.

Fig. 1

Peptide assembly by a non-ribosomal peptide synthetase. (a) An adenylation (Ad) domain catalyzes the activation of a specific carboxylic acid building block and acyl transfer onto a peptidyl carrier protein (PCP) domain. (b) A condensation (C) domain catalyzes coupling of two PCP-tethered acyl units, extending the peptide chain by one residue.

Fig. 2

Aryl-capped siderophores.

Fig. 3

(a) Reactions catalyzed by salicylate synthases (SS, e.g. Irp9) and isochorismate synthases (IS, e.g. EntC). (b) Designed inhibitors of an isochorismate synthase (E. coli EntC) and a salicylate synthase (Y. enterocolitica Irp9).

Fig. 4

Two-step reaction catalyzed by aryl acid adenylation enzymes, leading to aryl-capped siderophores.

Fig. 5

(a) Crystal structure of a phenylalanine adenylation domain (PheA) and bound conformations of phenylalanine and AMP ligands. (b) Crystal structure of a phenylalanyl-tRNA synthetase (PheRS) and bound conformation of a phenylalaninyl-AMP ligand. (c,d) Macrocyclic and linear aminoacyl-AMP analogs and inhibition of a cysteine adenylation domain (HMWP2¹⁻¹⁴⁹¹-His₆) and in vitro translation in rabbit reticulocyte lysates.

Fig. 6

MbtA adenylation enzyme-catalyzed covalent modification of the ArCP domain of MbtB using a vinyl sulfonamide analog of salicyl-AMP.

Fig. 7

(a) The 2,3-dihydroxybenzoyl moieties of enterobactin are iteratively C-glucosylated by IroB to form C-glucosylated enterobactin derivatives. (b) Bromoenterobactin analogs are potent inhibitors of IroB.

Fig. 8

(a) General structure of mycobacterial phenolic glycolipids (PGL) with p-hydroxybenzoic acid-derived moiety (red). (b) pHB-AMS is a tight-binding inhibitor of the p-hydroxybenzoic acid adenylation domain of the PGL biosynthetic enzyme FadD22.

Fig. 9

(a) Structure of a lipoteichoic acid with d-alanyl ester functionalities (red). (b) d-ala-AMS is an effective inhibitor of the d-alanine adenylation enzyme DltA.

Fig. 10

(a) AHL synthase-mediated biosynthesis of acyl homoserine lactones. (b) SAM analogs inhibit the P. aeruginosa AHL synthase RhII.

Fig. 11

(a) Biosynthesis of 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS). (b) Anthranilic acid derivative inhibitors of PQS and HHQ biosynthesis.