Tag: NTD

A new hope

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Although there’s a mountain of candidates, that’s not to say there haven’t been any promising leads. Earlier this year a team led by the Liverpool School of Tropical Medicine, and including chemists from Imperial College London, announced the discovery of a fast-acting, and highly effective compound. I’m not a chemist, or even a chemical biologist, but I think the drug discovery process is fascinating. The team took the initial ‘hit’ molecule and used it as a starting point to design an effective drug candidate (a process called lead optimisation). They derived a quinazoline, with a central core of two carbon rings fused together, and from this an azaquinazoline (i.e. modified to replace a carbon atom with a nitrogen atom).

The drug was modified further, including the addition of a trifluoromethyl group (see below, the side group with three fluorines and a carbon). Quinazoline derivatives such as this are often used to fight malaria and cancer; in this case the modifications made the drug more potent, and they called it AWZ1066S.

The trail of derivatives used to find AWZ1066S.
Image credit: Figure 1 from the paper by Hong et al. is licensed under CC BY-NC-ND 4.0

It meets the main criterion: it’s fast-acting, and treatment over a week leads to Wolbachia depletion of over 90%. This stops the worms from producing microfilaria, but the macrofilaricidal effect in humans is only predicted; it needs to be confirmed in clinical trials. Currently, the drug is in preclinical testing, to see if to see if it is safe for trial in humans.

Looking at the figure below, we can see that AWZ1066S is able to kill the majority of Wolbachia within just one day, an astonishing performance. The fact that it does this so much faster than other treatments suggests something profound: that it has a completely unique mode of action, a ‘first-in-class’ drug.

AWZ1066S outperforms all other treatments by a country mile.
Image credit: Figure 3 from the paper by Hong et al. is licensed under CC BY-NC-ND 4.0

This means that the drug will act fast enough to thwart bacterial resistance and, perhaps more importantly, the mode of action could be adapted to fight other bacteria. The trouble is, we don’t know what AWZ1066S targets in Wolbachia.

I asked Professor Ed Tate, from the Department of Chemistry at Imperial, and who led the work there. He’s also director of the Imperial Centre for Drug Discovery Science, responsible for “nucleating critical mass within the College” in the design of novel drugs—a rather curious mission statement, but of undeniable importance. He said:

“Knowing the target might let us ‘hop’ to the same target in other bacteria. If the target is novel then this could open up new ways to treat antimicrobial resistance in general. However, target identification in Wolbachia is very challenging thanks to the limited molecular cell biology and genetic tools available to undertake.”

The team did use chemical probes to identify some potential targets of the drug, but the problem still looms large: we don’t know how it works. Prof Tate says that finding this out would help determine “the risk of off-target effects both in humans and on other bacteria, and would help us make backup candidates in case the first drug meets problems in the clinic.”

Another boon to AWZ1066S is that it’s highly selective. This is a big advantage as the drug won’t kill the friendly gut bacteria, which play important roles in humans and other mammals. For example, Clostridium difficile is a commensal found in the gut (that is, they derive a mutual benefit from their hosts). They produce a compound called butyrate, which reacts with oxygen to produce carbon dioxide, lowering the oxygen concentration in the gut and making it harder for some harmful bacteria (which rely on the oxygen) to survive.

This is illustrated below: if an antibiotic (such as doxycycline) has off-target effects, these gut commensals may well be killed off, removing this very important line of defence. In these circumstances, nasty bugs gain the upper hand leading to some unpleasant side effects.

The trouble with antibiotics that aren’t specific to their targets

The feature is so important, it was selected for from the start by ensuring that it killed only Wolbachia and not other common gut bacteria. However, Prof Tate said “we do not currently understand whyit is selective, because we have not yet understood the mechanism by which it works in the bacterium”. He goes on to explain that it could be due to a variety of reasons, including selective uptake and accumulation, different metabolism, or a particular version of a common protein that’s particularly susceptible to the drug in Wolbachia.

Image credit: “Statue of Nebhepetre Mentuhotep II in the Jubilee Garment” by Pharos is licensed under CC0 1.0

So, there you have it. A very promising look at just one of the candidates which might one day help rid the world of elephantiasis. After a shockingly long history of this disease in humans (an ancient Egyptian statue of Pharaoh Mentuhotep II, who ruled over 4000 years ago, features the characteristic swelling), we are on the brink of its elimination. On behalf of the millions of people who suffer from the disease today, I can safely say it won’t be missed.

Target: elimination

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In an earlier post, I outlined WHO’s goal to be free of elephantiasis by 2020. Global elimination efforts currently rely on multiple rounds of mass drug administration, where doses of medicine are given to entire populations on an annual basis. This is preventative treatment (controlling the spread of parasites), and has worked quite well, as we have seen. In the past, the recommended regimen involves a combination of two antibiotics that target the larval stage, diethylcarbamazine and albendazole.

They are capable of clearing almost all microfilariae from the blood, but come with some unfortunate side effects including fever, headache and dizziness. Making matters worse, the adult worms are long-lived. To break the transmission cycle by killing only larvae requires prolonged drug delivery with extensive coverage; hardly ideal in countries where resources are scarce. Instead, drugs that target the adult worms are desperately needed.

I’ve talked about how the worms rely on their bacterial symbionts for survival, making Wolbachia an obvious target in the elimination of elephantiasis: if you stop the bacteria, you also kill the worm. This has been demonstrated with doxycycline, an antibiotic which belongs to the tetracycline family of antibiotics. These work by binding ribosomes, an important cellular factory, thereby stopping the bacteria from making proteins and reproducing.

Ball-and-stick model of the doxycycline molecule, a tetracycline antibiotic.
Image credit: “Doxycycline 3D ball” by Jynto is licensed under CC0 1.0

Crucially, doxycycline is more effective than the combined treatment, and has none of the problematic side effects as it eliminates the adult worms. Through this novel method of targeting the symbiont, treatment reduces the level of Wolbachia to a level where adult female worms became infertile: a safe, macrofilaricidal treatment.

Doxycycline is the best drug treatment we have, but it has two standout problems: it can be harmful to children and pregnant women, and it takes at least four weeks to work. But, since the drug concept has clinical evidence to support it, the idea has taken off. The initiative was granted funding from the Bill & Melinda Gates Foundation, giving rise to the Anti-Wolbachia Consortium, A·WOL. Their headquarters are at the Liverpool School of Tropical Medicine, and you can see the team in the video below, squashing mosquitos:

Infected abroad: Mosquito Bites by AWOL Wolbachia

The real goal here is to find a treatment which clears infection in under a week. To this end, A·WOL has screened over 2 million compounds, an onerous task. They’ve since identified 20,000 candidates, all active against Wolbachia, and ready for further investigation. That’s pretty much where we are today, with people in lab coats wading through a pile of ‘drug-like compounds’ in search of something that meets the criteria.

What can we do about it?

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Elephantiasis is an NTD: a neglected tropical disease. Although I think that the term falls victim to a desire in the sciences to give every concept a snappy abbreviation, this particular term encompasses a diverse array of nasty diseases, of which elephantiasis is the oldest known and most debilitating.

In light of this, the World Health Organisation (WHO) launched a global elimination programme in the year 2000, with the target completion date set for 2020. I’ll go into further detail in a later blog post, but in essence, the programme consists of large-scale preventative treatment in high risk areas, to complement direct treatment of those infected. It’s a colossal effort, but WHO claims that annual treatments over a period of 5 years will displace the disease from any given area. In aid of this, nearly 7 billion treatments have been handed out since 2000. That’s a staggering number.

To see how effective it has been, let’s look at the numbers: when the programme began there were more than 120 million people infected, and this has since declined to just under 40 million (the latest estimate); a considerable drop of about two thirds. Still, there are 900 million people who remain at risk, so committed nations need to keep up the pressure. These figures also make the target date of 2020 seem rather unrealistic, although WHO maintains that, by then, every single country where elephantiasis is commonplace will be free of transmission (or at least in post-intervention surveillance). So there is hope, not least because of a growing arsenal of anti-filarial drugs: stay tuned for when I talk to one of the scientists spearheading this work.