A Kryptonite for Pathogens
Could antibiotics that target virulence factors be the key to defeating multi-drug resistant “bugs of steel?”
Timothy Wencewicz |
At a Glance
- Battling antibiotic resistance is increasingly difficult as more and more pathogens evolve resistance to traditional antibiotics
- One way of defeating this is to target virulence factors, rather than whole pathogens, sidestepping the evolution of resistance
- Virulence factors affect a bacterium’s ability to infect or damage a host, rather than its ability to survive
- Targeting such pathways may yield non-traditional antibiotics that are more powerful and versatile than our current antimicrobials
For any pathologist working with infectious diseases, “superbugs” are a well-known and ever-increasing threat. These pathogens have developed resistance to multiple antibiotics – in some cases, to every antibiotic drug we possess. Naturally, this kind of resistance is a significant threat to patients, especially in cases of immunosuppression or frequent visits to doctors or hospitals. But how can we defeat it? Antibiotic development is slow, and resistance evolution is fast. Worryingly, it takes only a year or two after a new drug is introduced – sometimes less – for resistant strains to emerge in the clinic. So how can we fight an enemy that regenerates so rapidly? One answer is by targeting virulence factors, rather than targeting the growth or survival mechanisms of the pathogens themselves.
A. baumannii is a Gram-negative coccobacillus that acts as an opportunistic pathogen. Like other Acinetobacter species, it lacks cytochrome c oxidases, but possesses a number of virulence factors and determinants, including pathogenicity islands, beta lactamases, protective polysaccharide capsules, efflux pumps, and adhesion proteins. As a result, A. baumannii infections are often multi-drug resistant, and treatment frequently relies on polymixins – drugs so nephrotoxic that they’re considered a last resort in most patients.
Timothy Wencewicz and his team focus their research on the ability of A. baumannii to secrete siderophores that enhance the organism’s ability to scavenge iron from its host. Pre-acinetobactin is a siderophore most effective at acidic pH (<6.0). When the pH is higher, the siderophore undergoes a pH-triggered isomerization to become acinetobactin, which is most effective at basic pH (>7.0). It’s a “two-for-one” deal for the bacterium, ensuring that it retains its ability to sequester iron regardless of the pH of the host environment.
It’s possible that this strategy occurs in other bacteria as well; pre-acinetobactin is not the only siderophore to isomerize. But understanding how these molecules function may pave the way to targeting them with antibiotics. Of course, this is just the first step in a long journey from molecular understanding to clinical applications. But in a world where drug resistance is a looming threat and A. baumannii is a challenging opponent, a better understanding of what we face may be the key that eventually unlocks the ability to defend ourselves against it.
There are two main types of “magic bullet” antibiotics that have dominated the clinic for the past 75 years: bacteriostatic and bactericidal antibiotics. Both fit the general definition of an antibiotic; a substance that halts the growth of bacteria or kills them outright. Bacteriostatic antibiotics stop bacteria from growing, which prevents the infection from spreading but still relies on the immune system to clear the pathogen. Bactericidal antibiotics kill bacteria outright and actually decrease the bacterial load associated with an infection, without needing direct assistance from the immune system. But these treatments come with a clear downside – both types of agent put strong selective pressure on a bacterial population, creating an environment that allows resistant bacteria to overcome their normally susceptible companions.
The entire antibiotic industry was built on the discovery and development of these traditional types of antibiotics. Hospitals’ infectious disease departments were built around prescribing these types of antibiotics. Now, several factors are challenging the global antibiotic infrastructure: the rapid rise in antibiotic resistance, the decline in antibiotic discovery, and the depletion of effective prescription antibiotics. In the past decade, Big Pharma and federal funding institutions have placed significant emphasis on finding new, non-traditional antibiotics that apply less selective pressure (and are thus less likely to prompt the evolution of resistance) – a tall order considering resistance has been happening for hundreds of millions of years and will continue to happen as long as life is present on Earth. Nonetheless, this is when the concept of antivirulence antibiotic strategies truly began to gain traction.
Answers in antivirulence
Antivirulence antibiotics target bacterial pathways that are specific for pathogenesis or host invasion. These pathways aren’t needed for the day-to-day life processes of bacteria when growing in a test tube; they’re only activated when the pathogen attempts to establish itself inside a host. So in a host environment, antivirulence antibiotics behave like bacteriostatics – but in a “test tube” situation, they have no antibiotic effects at all. As good as that sounds, it gets straight to the heart of why we don’t currently have antivirulence antibiotics in the clinic. The platform that companies use to discover traditional antibiotics relies on screening large libraries of molecules in assays that test for direct inhibition of bacterial growth in a test tube. It’s far more challenging to develop assay conditions that mimic the human infection environment – but that’s what we would need to find new antivirulence antibiotic lead compounds.
It also doesn’t help that, inherent in the screening assay design, there’s a lack of understanding of the fundamental pathways that drive virulence. Personally, I support revamping the entire antibiotic pipeline, not only for non-traditional antibiotics like antivirulence compounds, but also for traditional “magic bullets.” Both will have a place in the long-term management of the global antibiotics market, and academic researchers like me can contribute by exploring new biological pathways, validating new targets and synthesizing new chemical structures that address as-yet unmet needs. My lab, for instance, studies iron acquisition pathways in bacteria. Because the battle for scarce iron can determine the overall course of an infection, many researchers consider these pathways the Achilles heel of pathogens.
Our research focuses on working out the fine details of how bacterial virulence systems function at the molecular level. We plan to use the natural molecules involved with bacterial iron scavenging from the host as starting points for building molecules that compete with and ultimately block the natural pathway. We are currently focused on the multi-drug resistant Gram-negative bacterial pathogen Acinetobacter baumannii, which uses a cocktail of four siderophore (iron-carrying) molecules for scavenging iron in the human host. Our recent research (1) has revealed the pH-triggered mechanism these bacteria use for iron acquisition – but more than that, it highlights our approach to understanding the molecular mechanisms of virulence. Hopefully, this kind of research lays the groundwork for establishing predictive antivirulence assays, so that one day we’ll be able to screen for “kryptonite” molecules that turn super-pathogens into ordinary Clark Kent bugs.
In the human body, antivirulence antibiotics behave like bacteriostatics – with one significant difference. Bacteriostatics halt pathogen growth by inhibiting a pathway required for primary life processes – but this creates more selective pressure, inducing resistance. Antivirulence antibiotics halt growth by inhibiting pathways required for invasion of host tissue or evasion of the immune system. Those aren’t primary life processes outside the host environment, so they don’t select for resistance in the same way.
The exact mechanism by which antivirulence antibiotics and the immune system work together to clear infection is difficult to predict and highly dependent on the antivirulence strategy. For example, we can block the production of a virulence factor that allows the pathogen to evade the immune system; then, the pathogen is no longer able to enter “stealth mode” and the immune system can successfully detect and clear it. In my laboratory, we block iron acquisition pathways and essentially “starve out” the pathogen, holding it hostage in a non-virulent state and buying time for the immune system to clear it naturally.
All human bacterial pathogens are susceptible to antivirulence antibiotics, but not all in the same way. Virulence pathways are unique to each pathogen because they’re tailored to enable pathogenesis in a specific tissue and environment. Although some strategies are more widely applicable than others, the general thought in the field is that antivirulence antibiotics should be tailored to a target pathogen. That’s both a scientific and an economic challenge, because it narrows the market for the drug and demands rapid and accurate diagnosis of the pathogen in question. The reason we so often use broad-spectrum antibiotics is because we lack good diagnostic tools for rapid bacterial identification. The opposite face of that argument is that narrow-spectrum antivirulence antibiotics are attractive from a resistance standpoint, because the selectivity of the target pathway protects other bacteria – including the healthy human microbiome. Our hope is that diagnostic science will keep up with the development of non-traditional antibiotics, so that we can use these tools in tandem against the growing threat of superbugs.
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- JA Shapiro, TA Wencewicz, “Acinetobactin isomerization enables adaptive iron acquisition in Acinetobacter baumannii through pH-triggered siderophore swapping”, ACS Infect Dis, 2, 157–168 (2016).