Rationally designing antisense therapy to keep up with evolving bacterial resistance

Abstract

Antisense molecules used as antibiotics offer the potential to keep up with acquired resistance, by redesigning the sequence of an antisense. Once bacteria acquire resistance by mutating the targeted sequence, new antisense can readily be designed by using sequence information of a target gene. However, antisense molecules require additional delivery vehicles to get into bacteria and be protected from degradation. Based on progress in the last few years it appears that, while redesigning or finding new delivery vehicle will be more difficult than redesigning the antisense cargo, it will perhaps be less difficult than finding new conventional small molecule antibiotics. In this study we propose a protocol that maximizes the combined advantages of engineered delivery vehicle and antisense cargo by decreasing the immediate growth advantage to the pathogen of mutating the entry mechanisms and increasing the advantage to the pathogen of antisense target mutations. Using this protocol, we show by computer simulation an appropriately designed antisense therapy can potentially be effective many times longer than conventional antibiotics before succumbing to resistance. While the simulations describe an in-vitro situation, based on comparison with other in-vitro studies on acquired resistance we believe the advantages of the combination antisense strategy have the potential to provide much more sustainability in vivo than conventional antibiotic therapy.