Antibacterial Discovery and Development: From Gene to Product and Back

Abstract

Concern over the reports of antibiotic-resistant bacterial infections in hospitals and in the community has been publicized in the media, accompanied by comments on the risk that we may soon run out of antibiotics as a way to control infectious disease. Infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Clostridium difficile, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and other Enterobacteriaceae species represent a major public health burden. Despite the pharmaceutical sector's lack of interest in the topic in the last decade, microbial natural products continue to represent one of the most interesting sources for discovering and developing novel antibacterials. Research in microbial natural product screening and development is currently benefiting from progress that has been made in other related fields (microbial ecology, analytical chemistry, genomics, molecular biology, and synthetic biology). In this paper, we review how novel and classical approaches can be integrated in the current processes for microbial product screening, fermentation, and strain improvement.

Synthetic Tet-inducible small hairpin RNAs targeting hTERT or Bcl-2 inhibit malignant phenotypes of bladder cancer T24 and 5637 cells

“…For example, the new molecular diagnostic platform based on synthetic biology and the light-inducible system for control of gene activation have the potential to develop the biosensors [17] and can offer large tools to speed up the discovery and [18]. Although some related technologies are still in their infancy, they may still become great protection ways to improve global health in the future.…”

The global preclinical antibacterial pipeline

“…Natural products are mainstays of our current antibiotic arsenal, exemplified by the large group of β-lactam antibiotics, aminoglycosides, tetracyclines and macrolides. Modern technologies such as genome mining contribute to the discovery of new scaffolds, and technical innovations are revealing new chemistry and increased yields, all of which contribute to the revival of natural product programmes [27][28][29] . LpxC inhibitors, which target the first dedicated step in the synthesis of lipid A, have been explored since the mid-1990s but no drug has advanced yet beyond phase I clinical trials.…”

Metabolomics in Antimicrobial Drug Discovery: The Success of the Chemical Diversity

“…For that reason the utilization of toxicometabolomics in drug discovery is a powerful tool both in clinical as industry [41]. In this way, toxicometabolomics look for obtain data about of pathways of toxicity, as well as signatures of toxicity, this information have a broad number of uses in biological sciences [42], because can integrate toxicokinetics and toxicodynamics for create the toxome that have the ability of combine in a multivariate analyses time of exposure, a large diversity of compounds with high chemical diversity that can be expressed in microbial strains as the case of Streptomyces lividans, Streptomyces albus, Streptomyces avermitilis and Streptomyces coelicolor for improve the yield of metabolites [18]. Other biotechnological tool employ epigenetic modifiers (DNA methyltransferase and histone deacetylase inhibitors) for control the expression of biosynthetic pathways and increase the generation of biomolecules in fungi [19,20].…”