Some have dubbed it the "antibiotic apocalypse"; others have said the looming crisis of antimicrobial resistance is a bigger global threat than terrorism. This is prompting researchers to think outside the box, or even the pill packet, about other ways to treat certain kinds of infections. And one way is to fight fire with fire and use so-called "friendly microbes" as antibiotic factories that can applied to wounds where they defeat the overgrowing bad guys. Speaking with Chris Smith, Alan O'Neil is at the University of California, San Diego...
Alan - One of the main problems in medicine at the moment is the emergence of antimicrobial resistance in pathogens such as Staph aureus. And one of the issues is most pharma and biotech industries have ceased discovery of antimicrobial compounds due to the emergence of antibiotic resistance. And so one of the things that we try to do in our lab is try to identify new antimicrobials that could be therapeutically used. And also we try to identify the organisms themselves that produce these antimicrobials and use the antimicrobial isolates as a bacterial therapy approach. So, as opposed to just isolating and purifying the compounds for therapeutic applications, we actually seek to use these microbes themselves, which are commensal, healthy microbes, and then transplant them. For example, onto patients who have skin infections with these drug resistant bacteria.
Chris - Why would it be better to use the microbes themselves rather than a tube of cream, or pop a pill?
Alan - The issue with a lot of antimicrobials is that they have poor pharmacological properties. Some antimicrobials can be hydrophobic, poor solubility, poor penetration into the skin. So it's very hard to produce these antimicrobials and have them effective in the clinic. But instead, if we apply the bacteria that naturally produce these antimicrobials, we think that this would be a much better approach given that the bacteria should be able to colonise the skin, be stable over a period of time, and essentially have a longer period to outcompete the pathogen.
Chris - Indeed, it's a bit like taking the pharmaceutical company factory to the wound, isn't it? Because they're just going to churn out the stuff and make it at the site where it's needed. But how do you get rid of the microbes when their job is done? Are we not potentially at risk of solving one problem and creating another one?
Alan - So the approach that we take is really to look at the commensal microbes. These are the healthy microbes. They don't have any pathogenic activity. We make sure that these microbes are sensitive to common antibiotics. The other benefit is that these microbes tend to produce bacteriocins, these antimicrobial peptides, which tend to have much more selective activity against the pathogen. So, due to that activity where it's not a broad spectrum where you're targeting the entire microbiome and killing everything on the skin, it's much more selective and specific. So in that case, we tend to think of these microbes being much more beneficial and having a much more holistic approach that you can reestablish a healthy commensal microbiome after applying these bacteria.
Chris - How have you actually approached this then?
Alan - We have different animal models that we use. So mice infected with Staph pseudintermedius and after applying the pathogen onto the skin of mice, we normally see a lot of redness scaling erythema. And after we apply the Staph felis, this antimicrobial isolate, we see that the redness goes down, the colonisation rates of the pseudintermedius strain also goes down and we see a therapeutic benefit here. We've also used other commensal Staph microbes, such as Staph hominis, and we've already done small phase one clinical trials in humans where we've applied the Staph hominis onto skin of human atopic dermatitis patients. And we've seen good clinical benefit after applying these bacteria onto skin.
Chris - Do the microbes you're applying actually kill off or drive out the infecting organism, or do they achieve their effect by modulating the skin's repair capacity or changing the way the immune system is working in that patch of skin? Or is it combination of these factors?
Alan - We think it's probably a combination of these factors. For sure, the important component of this approach would be the antimicrobials that these bacteria secrete into their environment would definitely have a very strong effect in limiting the growth and the survival of the pathogens. But we also know these antimicrobials also can exhibit anti-inflammatory activity too.
Chris - Given how common skin infections are and other problems where you get overgrowth of the wrong sorts of microbes, how far away are we from doing what you are doing and actually giving people basically a microbiome reset and treating their infection that way.
Alan - I think we're making really good progress on this and it will still take some time, but we are in phase two clinical trial at the moment in our lab with one of the antimicrobial strains. So we think this is a very powerful approach for certain infections. It would have difficulty, for example, in systemic infections, where of course you have an infection in the blood, but definitely for soft tissue infections we think that this could be a powerful approach.
Chris - Is it one size fits all, as in if I've got some skin inflammation or infection, and so have you, we would both slap on the same bug and treat it, or are you going to have to do horses for courses here and sort of tailor-make particular combinations of therapies for specific infections or specific people?
Alan - I think for specific infections, different microbes needing to be applied. But we know for certain skin diseases, for example, patients that suffer with atopic dermatitis, we know that they have a predisposition to Staph aureus colonisation and Staff aureus drives this disease. So it may be a case where we screen the patient first to identify which pathogen that they are actually colonised by. And once we identify that, that may dictate what type of antimicrobial isolate that we then apply. But we know that there are skin pathogens that very common in a lot of skin diseases. So we think that it won't be too diverse in terms of the antimicrobial isolates available.