Antimicrobial synergy between mRNA targeted peptide nucleic acid and antibiotics in E. coli.

A combination of antibacterial agents should make the emergence of resistance in bacteria less probable. Thus we have analyzed the synergistic effects between antibacterial antisense peptide nucleic acids (PNA) and conventional antibiotics against Escherichia coli AS19 (lipopolysaccharide defective) strain and a derivative of a pathogenic strain E. coli O157:H7. PNAs were designed to target mRNA transcripts encoding the essential acyl carrier protein (gene acpP) and conjugated to the cell-penetrating peptide (KFF)3K for cellular uptake. Antibiotics included aminoglycosides, aminopenicillins, polymyxins, rifamycins, sulfonamides and trimethoprim. Synergies were evaluated using the checkerboard technique. Fractional Inhibitory Concentration indices (FICi) were calculated for all combinations based on the minimal inhibitory concentration of each individual agent. The results demonstrate two novel synergistic combinations of antimicrobial agents, namely, (KFF)3K-PNA anti-acpP with polymyxin B and (KFF)3K-PNA anti-acpP with trimethoprim (both with FICi = 0.38). Polymyxin B's synergy postulates cell wall targeted antibiotics as attractive agents to improve the uptake of PNA while trimethoprim's interaction with PNA my reveal a new inhibitory mechanism.