From the Experts

Gene Editing Increases Antibiotic Production by Tenfold


Sr. Scientist

HudsonAlpha Institute for Biotechnology, USA

Antibiotics (anti-bacterial) are medications that either destroy or slow down the growth of bacteria. These are used to treat diseases caused by bacteria. The use of antibiotics started with discovery of penicillin, the first natural antibiotic, in 1928 by Alexander Fleming. Since then, new classes of antibiotics have been produced, particularly during the golden age of their discovery (1940 and 1960). Hence began an increase in the use of antibiotics for improving human health, with a subsequent increase in antimicrobial resistance that now poses a significant threat. Many synthetic antibiotics have failed to progress through clinical trials, leaving natural products as the only alternative. Half of the natural antibiotics are derived for filamentous actinomycetes, particularly Streptomyces species.

Streptomyces are primarily soil bacteria, and their ability to produce antibiotics makes them adapted to a wide range of environments. Streptomyces formicae is a strain of bacteria found in the nests of a species of African ant called Tetraponera penzigi. The ants use the antibiotic producing bacteria to protect themselves and their food source from pathogens.

Genomics revealed that bacterial and fungal species encode many biosynthetic gene clusters (BGCs). But, presently only 10% are being expressed under laboratory conditions. The genome of S. formicae encodes numerous specialized metabolite BGCs, including a type 2 polyketide synthase (PKS) that is responsible for the biosynthesis of formicamycins. These antibiotics are potent inhibitors of vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), with no resistance observed in vitro. It is shown that formicamycin (for) BGC makes two distinct families of compounds in addition to the formicamycins. 1. Fasamycins, that are biosynthetic precursors of the formicamycins and exhibit antibacterial activity. 2. Formicapyridines are shunt metabolites produced when the cyclization stage of the biosynthetic pathway is derailed.

Formicamycin BGC comprises 24 genes expressed on nine transcripts and is controlled by the combined actions of three cluster-situated regulators (CSRs). 1. The MarR-family transcriptional regulator ForJ that represses the expression of most of the biosynthetic genes, 2. ForGF is required to activate formicamycin biosynthesis. 3. MarR-family regulator ForZ, auto represses its own expression and activate expression of the putative, divergent MFS transporter gene forAA.

Previous work shows that Deletion of the forGF operon abolished the production of fasamycins and formicamycins in the wild-type strain. Here, deleting forJ increased formicamycin approximately 5-fold and Introducing a second copy of forGF into the ΔforJ mutant increased production of formicamycins to approximately 10 times the wild-type levels.

The formicamycins represent promising candidates as a new structural class of antibiotics, because of their ability to fight against drug-resistant pathogens and its high barrier for the development of resistance. This breakthrough overcomes the ability of Streptomyces formicae that only produces antibiotics in small quantities. In this new study1, researchers used CRISPR/Cas9 genome editing to make a strain that produces 10 times more formicamycins. The team used CRISPR/Cas-9 to make changes in regulatory genes and measured how much of the antibiotics were produced. This work not only increased the quantity of antibiotic produced but also the induction of biosynthesis in liquid culture, which forms the core for industrial production.

The discovery and development of new antibiotics is vital, given the increasing Antimicrobial resistance. The formicamycins are promising antibiotics that have little scope for development of resistance against. This work demonstrates the power of gene editing for improving human health in addition to its use for cure for diseases like sickle cell anemia.

Reference (Jan-21-A4)

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