Staph aureus and the neighborhood watch

Of all the bad bugs, S. aureus – Staph – is accounted among the worst. Several hundred thousand Americans suffer severe Staph infections every year and 30,000 die. If any bacterium deserves to be classified as a pest and a killer, a microbial reprobate beyond redemption, it is surely the grape-clustered golden spheres of Staphylococcus aureus.

But few bugs are all bad, and Staph is no exception. Most of the time it exists as a harmless commensal, inhabiting the moist surfaces of the nose and throat and armpit, causing no trouble at all. About 25 or 30% of North Americans carry Staph aureus, and few of us are ever bothered by it, much less sickened.

Bacteria are not necessarily germs. Of the 10,000 bacterial species that inhabit our bodies , fewer than a hundred are capable of causing disease. Most of these never do – they are apparently happy to exist, along with thousands of other bacteria, in a body that provides them with food and shelter. There are a few bugs, like Salmonella typhi, or Clostridium difficile, that are always looking for trouble, and will attack and invade our tissues to the best of their ability. They live by killing. The rest usually just try to find their niche and mind their own business within it.

This is well, because we are never rid of them. Staph, in particular, is not going anywhere. It has evolved along with us, and has an entire repertoire of molecular distractions, smokescreens and evasions that baffle our immune systems, including the ability to cloak itself with the agents sent to destroy it. Modern science has developed tools to teach our immune systems to recognize and destroy most other bacterial invaders. We have vaccines for Bordatella pertussis (whooping cough), Clostridium tetani (tetanus), Corynebacterium diphtheriae (diphtheria), Neisseria meningitidis (the usual cause of bacterial meningitis), Streptococcus pneumoniae (the cause of most bacterial pneumonia), Haemophilus influenza (another leading cause of pneumonia), Vibrio cholerae (cholera), Salmonella typhi (typhoid fever), and Bacillus anthracis (anthrax). But there is no vaccine for Staph. Despite decades of effort, the very mature and sophisticated science of vaccine development has found no means of rousing the immune system to detect and destroy it. It knows us too well.

Where the immune system fails, antibiotics succeed. Staph infections were among the first to be cured by penicillin. But the widespread use of penicillin led Staph to acquire ß-lactamase, an enzyme that breaks down penicillin, rendering the bacteria resistant. We countered this resistance by developing more stable forms of penicillin such as methicillin. The bacteria responded by acquiring an altered version of the molecular target of penicillins, and became resistant once more. This back and forth has continued over the succeeding decades until resistance to every clinically useful antibiotic has emerged in at least a few strains of Staph. Fortunately no strain has acquired all these resistances and become truly untreatable, but rates of resistance to several first-line antibiotics have become so high that initial treatment of serious infections is often ineffective or inappropriate.

The advent of microbiomics in the last decade has given us a new perspective on our relationships with bacteria, both in health and in disease. The logical endpoint to thinking of bacteria as germs is that they are invaders to be eliminated. In this view, antibiotics and antiseptics are to be used with abandon: killing germs improves health.

There is much that we do not understand about the human microbiome, but we do understand that this is not true. The use of antibiotics, which kill bacteria indiscriminately, has been linked to diarrhea, asthma, obesity, diabetes, heart disease, autoimmune disorders and other maladies. One might even argue – though I am not ready to go nearly this far – that antibiotics, as used in the last 50 years, have created more disease than they have cured.

Between rising rates of resistance and the increasing appreciation of the unwanted effects of microbiome disruption caused by antibiotic use, a new paradigm for treating bacterial infectious disease is beginning to take shape. Rather than kill or eliminate bacteria, we might seek to tame them instead; to turn rampaging vandals into sedate microbial citizens.

Staph aureus has a set of genes that are expressed when it is living as a peaceable commensal, and another set of genes that are expressed when it goes rogue and becomes an invasive pathogen. The citizen genes are those which increase its adherence to the skin, and allow it to make better use of resources in a low-nutrient environment such as healthy intact skin. In commensal mode, Staph aureus stays home, and thriftily makes do with the resources that are available.

In virulence mode, Staph releases toxins such as hemolysins (which rupture red blood cells to get at their iron, a limiting nutrient) and phenol-soluble modulins (which rupture white blood cells, provoke an inflammatory response, and promote biofilm formation). In sickness and in health, the same bacterium is present – it is its behavior that has caused disease, not its presence.

This distinction has significant implications for the development of new therapies. Anti-virulence therapy seeks to tame, rather than kill, bacterial invaders. It makes a distinction between the disease and the organism, suppressing the former without eliminating the latter. Because bacteria are not killed indiscriminately, the microbiome can continue to perform its services. And if bacteria are not killed, their incentive to develop resistance is greatly reduced. Medicine could get off the treadmill cycle of new drug discovery, followed by resistance development, followed by introduction of another new drug (or development of untreatable infections).

The microbiome itself is a likely source of anti-virulence therapeutics. A group of researchers from Texas Tech and Harvard recently did just this – they looked at the ability of the common and (usually) non-pathogenic skin commensal Corynebacterim striatum to suppress virulence in Staphylococcus aureus.

The researchers found that Staph grown in the presence of Corynebacteria shut down their virulence genes and turned on their commensal genes. The Corynebacteria did not have to be physically present – exposure to broth in which the Corynebacteria had grown and then been removed was sufficient to have the same effect.

In skin abcesses in mice, Corynebacteria suppressed the growth of Staph by a factor of six. In contrast, the Corynebacteria themselves did quite well – they grew twenty-fold more in abcesses that contain Staph than they did by themselves.

From Ramsey, Matthew M. et al. “Staphylococcus Aureus Shifts toward Commensalism in Response to Corynebacterium Species.” Frontiers in Microbiology 7 (2016): 1230. PMC. Web. 12 Sept. 2016.

And this behavior tells us something about why Staph may prefer to live as a commensal when other bacteria are around. Many of the bacteria that live a predominantly pathogenic lifestyle are intracellular invaders – they enter host cells, and feed off their resources in solitude. We could think of them as the kind of bank robber that sneaks into the bank, stealthily cracks the safe, and has the loot all to themselves. Staph doesn’t have the tools to be a safecracker – instead, it just blows up the bank, scattering the money all around. If the neighbors all are family – other Staph – so much the better. But if the neighbors are strangers and competitors, this means that they are getting a free ride on the released nutrients. They did none of the work and are getting most of the benefits, and use these benefits to outcompete and outgrow Staph.

This is perhaps why most of the virulence genes in Staph are controlled by quorum-sensing genes. These genes are used by Staph to determine who its neighbors are, by sensing whether molecules in its environment are being released by family or by competitors. If it’s the former, then maybe it is time to blow up the bank. If the latter, it is probably best to lay low until a better opportunity arises.

Getting Staph to lay low may be all that is required to treat invasive infections, particularly in patients with unimpaired immune systems. Clearly there are one or more molecules excreted by Corynebacterium into its growth medium that suppress virulence and enhance commensalism in Staph. The Texas Tech/Harvard researchers (and perhaps other groups) are searching for these molecules right now. These anti-virulence molecules could well be the basis for a new generation of anti-infective drugs that not only cure disease, but leave the microbiome intact as well. Rather than drop an antibiotic bomb that levels the neighborhood, we might be learn to encourage the kind of microbial community that keeps the delinquents in check without calling in the SWAT team.