Treating Before Infection?

We are sailboats on a bacterial sea; vessels separate from the microbial maelstrom until a crashing wave – infection – brings disease onto our decks. We bail out the infection with antibiotics, and the stability of the sailboat is restored.

Very poetic, but it doesn’t quite marry up to reality. We bail out infection with antibiotics but this doesn’t always restore the stability of the sailboat – in fact it can make it worse. Drug resistance is a rising tide and we need new options.

Inside the human body, there are ten bacterial cells for every normal cell, and their presence affects us on a daily basis. Bacteria confer many negative effects, including inflammation associated with eczema, acne and rosacea, and opportunistic infection following surgery due to skin colonization by pathogenic species. But every cloud has a silver lining; bacteria also have positive effects, such as protecting us from infections, synthesizing vitamins and assisting in the digestion of complex carbohydrates. In this very publication, Tim Sandle wrote about the complex relationship between we humans and our bacterial lodgers (1).

When dealing with bacteria, we often donn the silver lining until infection appears. And some will say, “why should we treat something before the negative effects become apparent?” However, I argue that there is room for pre-emptive treatment, before bacteria cause infection. At first, it may seem like a strange concept but there are many stages of bacterial interaction with the human body that eventually lead to infection. I call this the colonization–infection continuum. Every infection is preceded by colonization that may later lead to irritation, inflammation, local infection, and eventually systemic infection and sepsis.

The two major issues that prevent us from using antibiotics early on in this continuum are the fear of resistance, and the fact that antibiotics (particularly broad spectrum medicines) also kill millions of bacteria that do us good. We take this hit to our friendly bacteria when treating an infection because we are very unwell. If we want to treat earlier on a regular basis then we need treatments that are both specific to the target species of bacteria and that do not cause collateral damage to our microbiome. Such treatments open up many new options, such as sustainable prophylactic treatment before surgery or after small wounds, use of targeted-antimicrobials as maintenance therapy in recurrent skin infections like folliculitis and in chronic inflammatory skin conditions where particular species of bacteria are known to play a role (for example, Staphylococcus aureus), and even oral treatments designed to prevent harmful bacteria colonising the gut. Isn’t prevention the best treatment? In some cases, we could be hitting bacteria hard as soon as any signs of colonization are detected, such as in the early stages of irritation.

My day-to-day work involves endolysins. Endolysins are enzymes made by phages (viruses which naturally infect bacteria) and they are an essential part of the reproduction process of phages. Phages can replicate only through a bacterial host. When a bacterial cell is infected, the phage takes over its DNA and starts producing new phages. Many phages use endolysins, which are also produced inside the bacterial cell, to destroy the bacterial cell wall, releasing the new phages and killing the host bacterium.
They have three characteristics that assist in fighting antimicrobial resistance:

1. A working mechanism unrelated to that of antibiotics, meaning even antibiotic-resistant strains of bacteria, such as MRSA, are susceptible.
2. Phages have co-evolved with bacteria over millions of years; therefore, endolysins have naturally been selected to target highly conserved areas of the bacterial cell wall, greatly reducing the likelihood of bacterial adaptation.
3. Endolysins target specific bacterial species; when directed against the culprit pathogens, commensal (beneficial) bacteria are not killed, reducing the chance of opportunistic infection following treatment, as is often seen after courses of antibiotics.

I’ve been researching the potential that these molecules have in treating bacterial disease and in my view, they are a suitable candidate for using early on in the colonization­–infection continuum.

Research is ongoing into the full breadth of potential applications for endolysins, but they have already shown use in the maintenance of treatment for dermatological conditions such as acne, eczema and rosacea, where a bacterium has a role in inducing the inflammation. Also, recurrent infections like folliculitis and furunculosis can be controlled.

We are hopeful that in time, endolysin technology will become established in wound care, and eventually in the treatment of biofilm-related prosthetic joint infection; there is a great deal of exciting research still to be done. A great deal of what we read about the future of treating bacterial disease is very negative and apocalyptic, but I find working with endolysins very exciting. The technology has great potential and it’s a refreshing contrast to see a brighter future in microbiology on a daily basis.