There is increasing concern over the rise in antibiotic resistance, with many infections now becoming resistant not just to commonly used, long-established antibiotics like penicillin, but to last-resort newer antibiotics like vancomycin. The search for new antibiotics is becoming increasingly urgent – and it seems that some are lurking in surprising places.
The process of antibiotic resistance is a classic example of evolution in action: of the millions of bacteria that are susceptible to an antibiotic, if just one develops a gene mutation that enables it to survive, it will outlast its competitors and multiply rapidly. The intensive and often unnecessary use of antibiotics, coupled with the ability of bacteria to easily swap DNA between each other, has created what the World Health Organisation regards as a serious threat to human health: already, drug-resistant infections kill thousands every year. In the United States, for example, there are about 2 million resistant infections and 23,000 deaths a year (CDC).
It’s interesting to note that antibiotics themselves are often derived from other microbes – fungi, often, or even other bacteria. They are used by species against each other. Microbes that live in the soil have traditionally been a source of many antibiotics. This is because soil teams with communities of microbes from many thousands of species that are often in intense competition with each other (it’s not just dirt, it’s a jungle out there). Now researchers have discovered an antibiotic from a novel source: a bacterium that lives as a harmless commensal species inside the human nostrils. Yes, that’s right: up your nose.
Many people carry the bacterium Staphylococcus aureus in their nasal cavities: usually, it’s not a problem, but it is an opportunistic pathogen, and will cause disease given a chance. As the researchers note, in most cases of bacterial infections that spread throughout the body (and in many of the drug-resistant ones), the infective agent is one that is actually derived from species that naturally live on or in humans. We have a thriving microbiota – a little ecology – of bacteria living in our bodies, but if we are weakened, some of our residents can cause serious problems:
The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces…..and MDRO-colonized individuals are exposed to a substantially higher risk of invasive infections, that are difficult to treat, when they undergo surgery or immunosuppression or suffer from trauma….Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown.
The skin and upper airways are rich in bacterial species, but not necessarily rich in nutrients, suggesting that there might be strong competition for resources. So the researchers screened a range of Staphylococcus isolates from the nasal cavities and identified one, S. lugdenensis, which inhibited the growth of S. aureus. So far, so promising.
I should say that what followed next was a series of long, thorough and often difficult experiments to characterise firstly the gene responsible for this resistance, which involved a lot of mutation analysis, and then the structure of the protein coded for by the gene (to hypothesise how it worked), which involved a lot of analysis by chromatography, mass spectrometry….the usual candidates but a laborious process that I won’t detail here because I’ll be essentially repeating the paper. What all this hard work came up with was a totally new type of antibiotic, called lugdunin, which they’ve suggested should come under a grouping going by the catchy name of macrocylic thiazolidine peptide antibiotics. I’ve inserted figure 2 here as it is, essentially, the only one that is remotely pretty. A new class of antibiotics is exciting, because it points the way for finding other types of antibiotic in that class.
But how effective is it? And is it any good to us? Naturally, they looked further, screening it for anti-microbial activity against different strains of bacteria and determining if it was present in patients.
Lugdunin has potent antimicrobial activity against a wide range of Gram-positive bacteria, including opportunistic pathogens such as difficult-to-treat methicillin-resistant S. aureus [MRSA], glycopeptide intermediate resistant S. aureus and vancomycin-resistant Enterococcus isolates. Minimal inhibitory concentration (MIC) values in the micromolar range… demonstrated high potency, and this activity was not impaired in the presence of human serum…Bacterial cells exposed to lugdunin stopped incorporating radioactive DNA, RNA, protein or cell-wall precursors almost simultaneously even at concentrations below the MIC, suggesting that lugdunin may lead to rapid breakdown of bacterial energy resources
Wow, that’s good. What’s more, it didn’t affect some human cell types they tested, suggesting it wouldn’t be toxic. Even more strikingly, bacteria had difficulty generating resistance against this antibiotic:
Development of resistance was not observed in S. aureus during continuous serial passaging in the presence of subinhibitory concentrations of lugdunin over 30 days. In contrast, S. aureus rapidly developed resistance to rifampicin within a few days of exposure.
So what is this bacterium, S. lugdenensis, doing up our noses anyway? Well, it seems as if it has evolved to live there, and it produces this antibiotic to keep S. aureus and potentially other competitors at bay. In fact, if you have it, then you’re far less likely to have S. aureus, and this could be very helpful:
Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections….lugdunin has apparently evolved for the purpose of bacterial elimination in the human organism, implying that it is optimized for efficacy and tolerance at its physiological site of action. Thus, lugdunin shows promise as a potential drug for inhibiting growth of S. aureus in the nares [nose] and potentially other body sites.Moreover, human microbiota should be considered as a source for new antibiotics.
Yes, they should. And we should take a closer look at what our little residents are up to.
Zwitterer et al, 2016: Nature 535,511–516(28 July 2016) doi: 10.1038/nature18634.