Drug-resistant infections are a problem. Does it even need to be said? International campaigns have done their best to raise awareness, but even if all of humanity agreed to be on their best behavior, it seems the best we might do is slow the inevitable spread of already-identified resistance genes. Microbes have several advantages against our cleverest attempts: they multiply rapidly, they share genes readily, and there are just a dang lot of them. Last month, a gene that confers drug-resistance against the polymyxin colistin, the latest drug of last resort, was found to be widespread in China. How to stem the spread of these resistant infections?
It turns out human ingenuity may not be exhausted after all. And while discovering an entirely new class of antibiotics may take years of experimentation and development, the advances made in immunology may help increase our arsenal of antimicrobial compounds. For several decades, scientists have been studying the effects of antimicrobial peptides, generated by our own immune system. Some of these antimicrobial peptides are produced constitutively – at the same levels and at all times – while some are only made when infection is detected. There are many sorts of these molecules, and some are made in specialized tissues while others are made more generally.
One of these antimicrobial peptides, Histatin-5, has been well-characterized for its antifungal activity against Candida albicans. Histatin-5, or Hst-5, is a cationic molecule that interacts with the negatively charged microbial surface. Histatins are a family of peptides that are primarily found in the oral cavity, secreted in our saliva. Hst5 inhibits C. albicans mitochondrial respiration, which leads to the formation of dangerous reactive oxygen species, which damage the mitochondrial and cytoplasmic membrane and eventually lead to fungal cell death.
The ingenuity comes into play when considering a new application for histatins: administration via hydrogels embedded with recombinant Hst5 to membranous C. albicans infections. Researchers in Dr. Mary Ann Jabra-Rizk’s lab set out to test the efficacy of a such a hydrogel in an in vivo mouse model of oral candidiasis. Their results are now published in Antimicrobial Agents and Chemotherapy.
The scientists first developed a hydrogel made of nontoxic hydroxypropyl methycellulose, verified that Hst-5 diffuses from the gel, and observed a cell-density-dependent killing effect when applying the gel to an in vitro cell coculture. Gel applications were then tested in mice with oral candidiasis (also known as thrush). Untreated mice uniformly developed white plaques of Candida albicans on their tongues, while most treated mice did not develop visible fungal growth. In treated mice that did show signs of clinical disease, subsequent treatments with Hst-5 hydrogel were able to successfully treat it.
The need for additional antifungals is clear from the increase in drug-resistant C. albicans and other fungal isolates observed in hospitals and clinics. Successfully treating a mucosal infection such as thrush is a big step; the ability to treat patients systemically would be a big step forward toward decreasing deaths due to this dangerous infection. Another potential application is at indwelling catheter sites. C. albicans normally maintained on the skin can attach to these plastic devices, form biofilms, and potentially seed serious systemic infections. Administering a Hst-5 hydrogel near the places that these devices enter the body may help decrease both catheter colonization and subsequent bloodstream inoculation.
However, not all scientists think these innate molecules should be used as alternate antibiotics. The danger lies in microbial resistance: if fungi (or other microbes) become impervious to the effects of the immune system, infections will become yet more dangerous. Combine potential microbial resistance to both drugs and antimicrobial peptides, and a previously innocuous infection very quickly becomes potentially life-threatening. Nevertheless, our need for ways to deal with stubborn infections has us mining for therapies from every possible source, including our own immune system.
What do you think about the deployment of antimicrobial peptides as infection treatment? Leave your opinion in the comments section!
-- Julie Wolf