Plant synthetic biology for producing potent phyto-antimicrobials to combat antimicrobial resistance

Pragya Tiwari^a,1, Tushar Khare^b,c,1, Varsha Shriram^d,1, Hanhong Bae^a, Vinay Kumar^b,c

Molecular Metabolic Engineering Lab, Department of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.

Abstract

nappropriate and injudicious use of antimicrobial drugs in human health, hygiene, agriculture, animal husbandry and food industries has contributed significantly to rapid emergence and persistence of antimicrobial resistance (AMR), one of the serious global public health threats. The crisis of AMR versus slower discovery of newer antibiotics put forth a daunting task to control these drug-resistant superbugs. Several phyto-antimicrobials have been identified in recent years with direct-killing (bactericidal) and/or drug-resistance reversal (re-sensitization of AMR phenotypes) potencies. Phyto-antimicrobials may hold the key in combating AMR owing to their abilities to target major microbial drug-resistance determinants including cell membrane, drug-efflux pumps, cell communication and biofilms. However, limited distribution, low intracellular concentrations, eco-geographical variations, beside other considerations like dynamic environments, climate change and over-exploitation of plant-resources are major blockades in full potential exploration phyto-antimicrobials. Synthetic biology (SynBio) strategies integrating metabolic engineering, RNA-interference, genome editing/engineering and/or systems biology approaches using plant chassis (as engineerable platforms) offer prospective tools for production of phyto-antimicrobials. With expanding SynBio toolkit, successful attempts towards introduction of entire gene cluster, reconstituting the metabolic pathway or transferring an entire metabolic (or synthetic) pathway into heterologous plant systems highlight the potential of this field. Through this perspective review, we are presenting herein the current situation and options for addressing AMR, emphasizing on the significance of phyto-antimicrobials in this apparently post-antibiotic era, and effective use of plant chassis for phyto-antimicrobial production at industrial scales along with major SynBio tools and useful databases. Current knowledge, recent success stories, associated challenges and prospects of translational success are also discussed.

Keywords: Antimicrobial resistance (AMR), Computer-aided design, CRISPR-Cas, Genome editing, Metabolic engineering, Phyto-antimicrobials, Phytochemicals, Plant chassis, RNA-interference.