Enhancement of inhibition rate of antibiotic against bacteria by molecularly imprinted nanoparticles targeting alarmone nucleotides as antibiotic adjuvants.

Antibiotic tolerance and resistance in bacteria have caused a great threat to humankind. Bacteria can rapidly accumulate alarmone nucleotides (guanosine tetra- and pentaphosphate, usually denoted as (p)ppGpp) to repair damaged DNA under adverse conditions. The inhibition synthetase enzyme activity of (p)ppGpp, indirectly preventing synthesis, or promoting degradation, has been reported; however, transferring these strategies to practical applications is still a challenging task due to the lack of highly effective molecules for these purposes. Here, an approach based on molecularly imprinted polymer nanoparticles (MIP-NPs) as antibiotic adjuvants was proposed, where MIP-NPs with specific recognition sites were used to capture alarmone nucleotides released by bacteria during stringent response activation. Enhanced inhibition rates of 40-80% were achieved in the presence of the MIP-NPs. The dose of antibiotic could be greatly reduced by utilizing the MIP-NPs as adjuvants for a similar deactivation effectiveness. Good biocompatibility (no obvious hemolysis or cytotoxic effects) and apparent antimicrobial efficiency for resisting wound infection in vivo support the fact that well-designed MIP-NPs have a bright future in dealing with the growing threat of antibiotic tolerance and resistance.