When you hear/ read the term “Phage Therapy“, you’ll be automatically directed to the concept of using bacteriophages, the virus-like particles that infect bacteria, to kill/ lyse the resistant bacterial strains, instead of the “useless” antibiotics that allowed bacteria to fool them & develop resistance against them. The initial target of phage therapy was to kill the bacteria using phages; because they act like any other virus; get in, multiply and lyse the cell. But, by this way, bacteria develop resistance against phages more rapidly. So, they may become useless by time. In this paper from PNAS: “Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy,” two bioengineers, Timothy K. Lua and James J. Collins, from Boston University successfully engineered the Enterobacteria filamentous phage M13 to weaken bacteria not to kill it. Sounds strange, right? By engineering M13, they gave us a variety of options:
1st, we may make M13 overexpress a bacterial protein named lexA3 which inhibits the ability of the bacteria to repair their damaged DNA by the action of Ofloxacin –as pharmacophils, who had 2 consecutive chemotherapeutics courses, we may recall that quinolones’ MOA is generation of ROS. So, the repressor suppresses the bacterial SOS mechanism. Very promising results were observed; the adjuvant therapy increased the survival rate of mice infected with resistant E. coli. It was also observed that the adjuvant therapy reduced the rate of developing mutations/ resistance within the E. coli population.
2nd, bacteriophage can be responsible for expression of certain proteins that can attack gene networks in bacteria which are not target for existing antibiotic classes. I will mention just one example here, expression of CsrA which is a “global regulator of glycogen synthesis and catabolism, gluconeogenesis, and glycolysis, and it also represses biofilm formation,” biofilms is thought to be related to antibiotic-resistance and OmpF porin which is used by quinolones to enter the bacterial cell, it may enhance its entrance.
Now, thanks to the engineered phages, we can use the old beloved antibiotic classes to treat bacterial infection using the engineered phages as an adjuvent therapy to potentiate the cidal action of the antibiotic on the former-resistant strains. A precaution was made to ensure that no lysogeny would take place in the human cells is that the phages were engineered to be “nonreplicative”. But we still have two problems regarding Phage Therapy in general: identifying the strain responsible for the infection & making sure that the human immune system won’t elicit an immune response against phages, they’re “foreigners” after all!
1- “Schematic of combination therapy with engineered phage and antibiotics. Bactericidal antibiotics induce DNA damage via hydroxyl radicals, leading to induction of the SOS response. SOS induction results in DNA repair and can lead to survival. Engineered phage carrying the lexA3 gene (lexA3) under the control of the synthetic promoter PLtetO and an RBS acts as an antibiotic adjuvant by suppressing the SOS response and increasing cell death”: http://www.pnas.org/content/106/12/4629.figures-only
2- “CsrA suppresses the biofilm state in which bacterial cells tend to be more resistant to antibiotics. OmpF is a porin used by quinolones to enter bacterial cells. Engineered phage producing both CsrA and OmpF simultaneously (csrA-ompF) enhances antibiotic penetration via OmpF and represses biofilm formation and antibiotic tolerance via CsrA to produce an improved dual-targeting adjuvant for ofloxacin”: http://www.pnas.org/content/106/12/4629.figures-only
, engineered bacteriophage
, phage therapy