Oxacillin Coupled G-Quadruplexes as a Novel Biofilm-Specific Antibiotic for Staphylococcus aureus Biofilms

Abstract

One of the most important traits of pathogenic microbial biofilms is their high tolerance to conventional antimicrobial agents, which is partially due to the presence of metabolically inactive and transiently resistant persister cells. Here, we use guanine-rich DNA structures known as G-quadruplexes (G4s) coupled with the β-lactam antibiotic, oxacillin (OX), and loaded with an iron-containing protoporphyrin IX (hemin), as an OXG4/hemin complex biofilm-specific antibiotic agent. By coupling the OX to the G4, to form an OXG4/hemin complex, the diffusion of the OX was facilitated into the biofilm. Further, by utilizing the known oxidizing behavior (peroxidase-mimicking) of the G4/hemin complex the entire system was found to be highly effectively against Staphylococcus aureus biofilms. By using G4 structures to penetrate biofilms, this work paves the way for an entirely new DNA-based therapy for biofilm eradication.

Approaches for the inhibition and elimination of microbial biofilms using macromolecular agents

“…One example is given by Ellis, Locock and Qu et al, who prepared antibiofilm materials from guanine-rich DNA sequences that can assemble into three-dimensional complexes known as G-quadraplexes. 202 These DNA sequences could be coupled to a b-lactam antibiotic, oxacillin, and complexed with the iron-containing protoporphyrin IX (hemin) to form a drug conjugated oxacillin-G-quadraplex-hemin complex. Given the oxidoreductase capability of the iron present in hemin, this species can mimic the enzymatic activity of peroxidases through the production of reactive, oxidized species such as hypothiocyanite ([OSCN] À ) in the presence of hydrogen peroxide.…”

“…Whilst more mechanistic investigation is required to fully elucidate the various modes of action, taken together, these findings demonstrate how the catalytic nature of hemin, along with the enhanced biofilm penetration of the DNA-drug conjugate, could be used to synergistically eliminate established biofilms. 202 For more information on non-macromolecular enzyme mimics for biofilm eradication, such as inorganic nanoparticles, the reader is referred to the following text. 203…”