Title: Bio-Orthogonal Chemistry and Reloadable Biomaterial Enable Local Activation of Antibiotic Prodrugs and Enhance Treatments against Staphylococcus aureus Infections
Authors: Magdalena Czuban, Sangeetha Srinivasan, Nathan A. Yee, Edgar Agustin, Anna Koliszak, Ethan Miller, Irfan Khan, Ilenis Quinones, Hasina Noory, Christopher Motola, Rudolf Volkmer, Mariagrazia Di Luca, Andrej Trampuz, Maksim Royzen, and Jose M. Mejia Oneto
Journal: ACS Central Science
Bacterial infections have emerged as a major threat in the modern era thanks to the rapid evolution of drug-resistant microorganisms. Scientists are constantly engaged in a bacterial arms race as they strive to develop novel antibiotics that are capable of destroying increasingly resilient bacteria. These “superbugs” have significantly slowed the pace of drug discovery in the past few decades, forcing researchers to search for alternative methods to improve patient treatment outcomes. One approach relies on employing targeted drugs to specifically treat localized bacterial infection — a problem that is becoming increasingly common in surgical implant procedures. This targeted approach reduces the negative side effects associated with widespread dosage, including the unintentional loss of native microbiota that are crucial for human health. A targeted system also creates an increased bacterial exposure area for antibiotics and allows multiple rounds of treatment. These higher drug levels could help prevent the “escape” of partially resistant bacteria that might go on to produce even more virulent strains.
In this study, scientists sought to increase drug efficacy and reduce harmful side effects by developing a site-specific, chemically-activated system. This system relied on the use of a particular type of Diels-Alder chemistry (or “click” chemistry). One can think of this reaction as having two pieces: the tetrazine (Tz) piece and the trans-cyclooctene (TCO) piece (Figure 1A, B). These pieces do not react with other materials within the body and will “click” together in a highly favorable reaction once the two are in close proximity (Figure 1C). The researchers used a Tz-modified alginate gel (TAG) as a targeting platform and created two prodrug TCO-antibiotics which are inactive unless the click reaction takes place. After clicking together, the active drug is released from the hydrogel over a period of time, allowing researchers to add multiple prodrug doses to the TAG (Figure 1C, D).
Figure 1: Schematic illustrating bioorthogonal, chemistry-based strategy for targeted antibiotic treatment of bacterial infection. (A) TAG injected into infected area. (B) TCO-modified prodrug delivered to patient. (C) Prodrug and TAG come into close proximity, leading to click reaction. (D) Active drug is released into site of infection. (Figure caption adapted from original paper).
After validating drug efficacy and release in vitro for the antibiotics vancomycin and daptomycin, the researchers decided to conduct initial tests in mouse models. They tracked drug and hydrogel processing through fluorescent labeling to ensure that the treatment remained localized and found that TAG elicited no harmful response in the mice other than mild inflammation. Finally, the authors conducted a test with TAG+TCO-vancomycin injected with a batch of fluorescent methicillin-resistant Staphylococcus aureus (MRSA). They found that the TCO-vancomycin caused an 800-fold reduction in bacterial load, outperforming previous tests in vitro and leading to a clear change in fluorescence (Figure 2).
Figure 2: TAG + TCO-vancomycin eliminates bacterial infection in mice in 24 hours. (A) Images of mice injected with fluorescently-labeled gels (red) with TAG or a negative control (UG) and MRSA bacteria (blue) at 6 and 24 hours. (B) Bacterial load in the collected tissue from the three sets of mice. (Figure caption adapted from original paper).
These results are extraordinarily promising and could dramatically change the way that localized infections are treated in the future. Similar hydrogel delivery methods have previously had some success for site-specific delivery of oncology medications and this approach clearly translates well to antibiotic applications. We can only hope that further research will produce similarly exciting results in human subjects, providing an alternative combat strategy for the ever-looming threat of bacterial drug resistance.