Applications and Perspectives of Cascade Reactions in Bacterial Infection Control

Abstract

Cascade reactions integrate two or more reactions, of which each subsequent reaction can only start when the previous reaction step is completed. Employing natural substrates in the human body such as glucose and oxygen, cascade reactions can generate reactive oxygen species (ROS) to kill tumor cells, but cascade reactions may also have potential as a direly needed, novel bacterial infection-control strategy. ROS can disintegrate the EPS matrix of infectious biofilm, disrupt bacterial cell membranes, and damage intra-cellular DNA. Application of cascade reactions producing ROS as a new infection-control strategy is still in its infancy. The main advantages for infection-control cascade reactions include the fact that they are non-antibiotic based and induction of ROS resistance is unlikely. However, the amount of ROS generated is generally low and antimicrobial efficacies reported are still far <3-4 log units necessary for clinical efficacy. Increasing the amounts of ROS generated by adding more substrate bears the risk of collateral damage to tissue surrounding an infection site. Collateral tissue damage upon increasing substrate concentrations may be prevented by locally increasing substrate concentrations, for instance, using smart nanocarriers. Smart, pH-responsive nanocarriers can self-target and accumulate in infectious biofilms from the blood circulation to confine ROS production inside the biofilm to yield long-term presence of ROS, despite the short lifetime (nanoseconds) of individual ROS molecules. Increasing bacterial killing efficacies using cascade reaction components containing nanocarriers constitutes a first, major challenge in the development of infection-control cascade reactions. Nevertheless, their use in combination with clinical antibiotic treatment may already yield synergistic effects, but this remains to be established for cascade reactions. Furthermore, specific patient groups possessing elevated levels of endogenous substrate (for instance, diabetic or cancer patients) may benefit from the use of cascade reaction components containing nanocarriers.

Controlled drug delivery systems in eradicating bacterial biofilm-associated infections

“…Moreover, in inflammatory conditions induced by microbe infection, the pathogens may secrete factors that increase the permeability of blood vessels [106]. Therefore, the nanoparticles with diameters less than 200 nm could passively accumulate at the infected sites due to the enhanced permeability and retention (EPR) effect [107], similar to that found in tumor sites [108]. Upon reaching the sites of infection, the antimicrobial-loaded delivery systems need to penetrate the extracellular polymeric substances of biofilms efficiently and bind to the embedded bacterial cells.…”

Activation of a passive, mesoporous silica nanoparticle layer through attachment of bacterially-derived carbon-quantum-dots for protection and functional enhancement of probiotics

“…In a next step however, the encapsulating shell might serve as a container for a non-living, chemically active interior, as in artificial cellular bioreactors [ 33 , 34 ]. For the development of fully engineered probiotic nanoparticles, the chemically active interior could be composed of cascade-reaction components [ 35 ], producing antimicrobials from endogenously present substances in the human body.…”

A Guanosine‐Quadruplex Hydrogel as Cascade Reaction Container Consuming Endogenous Glucose for Infected Wound Treatment—A Study in Diabetic Mice

“…Cascade reactions integrate two or more reactions and each completed reaction initiates the next reaction. [ 11 ] For use as a cascade reaction container, G 4 ‐hydrogels were loaded with glucose‐oxidase and hemin, to transform naturally occurring endogenous glucose into H 2 O 2 in the first, glucose‐oxidase assisted reaction. In the subsequent reaction, H 2 O 2 is transformed into ROS with the aid of hemin.…”