Using bacterial genomes and essential genes for the development of new antibiotics

Abstract

The shrinking antibiotic development pipeline together with the global increase in antibiotic resistant infections requires that new molecules with antimicrobial activity are developed. Traditional empirical screening approaches of natural and non-natural compounds have identified the majority of antibiotics that are currently available, however this approach has produced relatively few new antibiotics over the last few decades. The vast amount of bacterial genome sequence information that has become available since the sequencing of the first bacterial genome more than 20 years ago holds potential for contributing to the discovery of novel antimicrobial compounds. Comparative genomic approaches can identify genes that are highly conserved within and between bacterial species, and thus may represent genes that participate in key bacterial processes. Whole genome mutagenesis studies can also identify genes necessary for bacterial growth and survival under different environmental conditions, making them attractive targets for the development of novel inhibitory compounds. In addition, transcriptomic and proteomic approaches can be used to characterize RNA and protein levels on a cellular scale, providing information on bacterial physiology that can be applied to antibiotic target identification. Finally, bacterial genomes can be mined to identify biosynthetic pathways that produce many intrinsic antimicrobial compounds and peptides. In this review, we provide an overview of past and current efforts aimed at using bacterial genomic data in the discovery and development of novel antibiotics.

New and developing diagnostic technologies for urinary tract infections

“…These advances enable the identification of pathogens by targeting pathogen-specific molecular signatures. Furthermore, genome sequence analysis is being used to understand mechanisms and patterns of antibiotic resistance 58 as well as provide tools for discovery of new antimicrobials 59 .…”

The therapeutic potential of bacteriocins as protein antibiotics

“…Farming industries, such as the poultry industry [21,69] and aquaculture industry [70], look for more efficient ways to treat their stock. Interest in human applications comes from scientists and companies that realize the global health and economic potential of bacteriocin therapeutics.…”

“…The potential of the latter two, CLBs and tailocins, to treat bacterial infections is reviewed here. Previous reviews have discussed Gram-positive bacteriocins as antibiotics [11,21,22] and the in vitro potential of bacteriocins against Gram-negative bacteria [11,[23][24][25]. Our aim is to focus on the potential ability of CLBs and tailocins to treat Gram-negative infections and give an exhaustive report of the results available from in vivo models of infection to date.…”

Novel antimicrobial peptide discovery using machine learning and biophysical selection of minimal bacteriocin domains

“…Many bacteria have become resistant to conventional antibiotics, necessitating the discovery of novel antimicrobial compounds (CDC, ). To combat the lack of novel antimicrobial discovery, many bioinformatic approaches have been developed to mine the genomes of bacteria for natural products (Fields, Lee, & McConnell, ). One promising class of natural products is bacteriocins, the ribosomally produced antimicrobial peptides of bacteria (Alvarez‐Sieiro, Montalbán‐López, Mu, & Kuipers, ).…”

“…Genome mining approaches capitalize on the bacteriocin operon-like structure to identify bacteriocin candidates through two approaches: identification of the bacteriocin precursor gene or identification of context genes (Fields et al, 2017;Hammami, Zouhir, Hamida, & Fliss, 2007;Morton et al, 2015;Van Heel, De Jong, Montalbá N-Ló Pez, Kok, & Kuipers, 2013). Online mining tools, such as BAGEL and BACTIBASE, allow investigators to identify and classify putative bacteriocins based on their homology to known bacteriocin genes (Hammami et al, 2007;Van Heel et al, 2013).…”