Increasing the success rate of lantibiotic drug discovery by Synthetic Biology.
BACKGROUND
Lantibiotics are post-translationally modified antimicrobial peptides produced by bacteria from diverse environments that exhibit an activity against pathogenic bacteria comparable to that of medically used antibiotics. The actual need for new antimicrobials in therapeutics has placed them in the pipeline of antibiotic research, due not only to their high antimicrobial activity but also to the fact that they are directed to novel targets.


METHODS
This review covers the different approaches traditionally used in bacteriocin discovery, based on the isolation of bacteria from different habitats and determining their inhibitory spectrum against a set of relevant strains. It also elaborates on more recent approaches covering organic synthesis and semi-synthesis of lantibiotics, genomic and proteomic approaches and the application of Synthetic Biology to the field of antimicrobial drug discovery.


CONCLUSIONS
Lantibiotics show a great potential in fulfilling the requirements for new antimicrobials. Culture-dependent techniques are still applied to lantibiotic discovery producing successful results that can be furthered by employing high-throughput screening techniques and peptidogenomics. The necessity of culturing bacteria and growing them in specific conditions for lantibiotic expression, can hamper the discovery rate, especially in exotic or unculturable bacteria. Thus, a combination of genome mining procedures, to detect novel lantibiotic-related sequences, with heterologous production systems and high-throughput screening, offers a promising strategy. Furthermore, the characterization of the mechanism of action of many lantibiotics, and the development of "plug and play" peptide biosynthesis systems, offers the possibility of initiating the rational design of non-natural lantibiotics based on structure-activity relationships.
University of Groningen, Molecular Genetics Group, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
Manuel
M
Montalbán-López
Liang
L
Zhou
Andrius
A
Buivydas
Auke J
AJ
van Heel
Oscar P
OP
Kuipers
D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000378:metabolism; D001430:Bacteriocins / Q000138:chemical synthesis* / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D013329:Structure-Activity Relationship; D058615:Synthetic Biology / Q000379:methods*
D000890:Anti-Infective Agents; D001430:Bacteriocins