From General to Specific: Can Pseudomonas Primary Metabolism Be Exploited for Narrow‐Spectrum Antibiotics?

Abstract

The spread of antimicrobial resistance is a major threat to human health, and patients requiring prolonged antibiotic exposure are in desperate need of new therapeutic strategies. It has been hypothesized that tailoring our antibiotics to inhibit molecular targets specific to pathogens might stem the spread of resistance. A prime candidate for such a strategy is Pseudomonas aeruginosa, which can be found in the lungs of nearly all adult cystic fibrosis patients and, due to chronic exposure to antibiotics, has a high rate of multidrug-resistant strains. Although much research has been done on P. aeruginosa virulence factors as narrow-spectrum targets, less attention has been paid to primary carbon metabolism being leveraged for pathogen-specific mechanisms. However, early studies show that primary metabolic pathways, although shared amongst all organisms, contain intricacies specific to Pseudomonas species that have potential for antibiotic exploitation. Here we lay out some of this work in the hopes that it inspires researchers to continue developing a knowledge base for future antibiotic discovery to build upon and include a case study of a Pseudomonas primary metabolic pathway that has been targeted by small molecules in a species-specific manner.

Central metabolism is a key player in E. coli biofilm stimulation by sub-MIC antibiotics

“…Mutations in some of the core metabolic genes identified from our screens ( icd, sucA, nuoM ) that confer antibiotic resistance have been identified in clinical isolates (Lopatkin et al, 2021), so inhibiting these targets might sensitize cells in addition to suppressing biofilm stimulation. Targeting these metabolic enzymes must avoid inhibition of their eukaryotic homologues, but careful design of narrow spectrum inhibitors of bacterial central metabolism is possible (Keohane et al, 2018; Shapiro, Kaplan, & Wuest, 2019). We also showed that nitrate suppresses biofilm stimulation by bactericidal antibiotics.…”

Recent Progress in Natural-Product-Inspired Programs Aimed To Address Antibiotic Resistance and Tolerance

“…Over the past several years, Wuest and co-workers have developed an exciting medicinal chemistry and chemical biology program around the species-selective agent promysalin 53 (Figure A), which targets the major Gram-negative pathogen Pseudomonas aeruginosa . ,− The multispecies community found in the root systems of various plants is known as the rhizosphere, , and in this environment, bacteria are known to utilize chemical warfare strategies for colonization and to defend themselves. Pseudomonads are highly prevalent in the rhizosphere, and these bacteria produce an array of secondary metabolites with biological activities that promote survival, including antibiotics, virulence factors, biosurfactants, siderophores (to obtain iron from their environment) .…”

“…Further validation that SdhC was the target of 53 was carried out in vitro and via whole genome sequencing of resistant mutants. These findings demonstrate that targeting the tricarboxylic acid (TCA) cycle could be useful in developing narrow, species-selective antibiotic therapies and warrant additional studies regarding SdhC as an antibiotic target. − …”

Towards Photochromic Azobenzene‐Based Inhibitors for Tryptophan Synthase

“…[2] Most antibiotics engage in bacterial cell-division processes or weaken the bacterial membrane. [3] Recently, the search for alternative targets was expanded to metabolic enzymes, [4] such as the well-investigated multienzyme complex tryptophan synthase (TS). TS catalyzes the last two steps of tryptophan biosynthesis in bacteria, plants, and fungi.…”