---
title: "My favourite polyfluorinated pyrethroid"
slug: "transfluthrin-resistance"
date: "09/07/2023"
thumbnail: '/thumbnails/tft.png'
tag: repellent 
canonicalUrl: 'https://sanjaycnagi.com/blog/transfluthrin-resistance/'
---

![mosquito_shield](/mosquito-shield.jpg)        
*Mosquito Shield™* - a novel transfluthrin-based spatial repellent product for the malaria vector control market (source: [SC Johnson](https://www.scjohnson.com/en/a-healthier-world/sc-johnson-combats-malaria))

---

A few words on the greatest polyfluorinated pyrethroid I’ve ever written a thesis about – Transfluthrin. Back in my first foray into vector control, I was working in Mumbai at [Godrej](https://godrej.com), looking at resistance to the main active ingredient in their flagship insect repellent brand, [GoodKnight™](https://www.goodknight.in/), for my MSc dissertation. With randomised-controlled trials (RCTs) of the SC Johnson product *Mosquito Shield™* ongoing in sub-Saharan Africa, now seems an opportune time to discuss some of those findings.

Transfluthrin is a vapour-phase pyrethroid often used in domestic household products, such as sprays and liquid vapourisers. It repels mosquitoes, as well as incapacitating them to prevent host-seeking and blood-feeding. It's been particularly popular in the South Asian market for several years, with South America seemingly playing catch up. And, in recent years, it's also been explored as a novel vector control tool for malaria.

#### Metabolic resistance to transfluthrin?

As well as resulting in its high vapour pressure compared to common pyrethroids, the fluorination of transfluthrin may make it somewhat resistant to metabolic attack from Cytochrome P450s. Typically, pyrethroids are metabolised at the 4' position of the phenoxybenzyl ring. In Transfluthrin, however, the electro-negative fluorines pull electrons away from its benzyl ring, in theory preventing attack by electron-hungry cytochrome P450s. 

---
![tft_metabolism](/tft_metabolism.png)  
A figure from my thesis '*Mechanisms of resistance to transfluthrin in mosquitoes', 2017*, supervised by Dr. David Weetman and Dr. Mark Paine. 

---

Earlier research from Bayer [[1]](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149738), had shown limited to no synergism with PBO in the FuMoz strain of *An. funestus*, suggesting that P450s could not metabolism transfluthrin. This was followed with a later study [[2]](https://www.sciencedirect.com/science/article/pii/S0048357523000214), showing that CYP6P9a/b could only metabolise transfluthrin very weakly, by targeting the gem-dimethyl group - as predicted in my thesis ;)

We demonstrated that this wasn't the case across species, however, with PBO synergising volatile transfluthrin in an Indian strain of *Culex quinquefasciatus*, and showing that the *An. gambiae* P450 CYP6P3 can metabolise transfluthrin *in vitro*. *In vitro* metabolism was much lower than for Deltamethrin, however, demonstrating transfluthrin's comparative ability to resist metabolic attack from P450s. It is not quite clear the role that other gene families, such as carboxylesterases or chemosensory proteins will play in transfluthrin resistance.

Given that PBO should still synergise transfluthrin in most resistant mosquito strains, the combination of PBO nets and a transfluthrin-based spatial repellent could be a useful combination for vector control. 


#### The effect of *VGSC* knockdown mutations on transfluthrin 

The "resistance-breaking" potential of transfluthrin doesn't end there. Although there is evidence that *Kdr* may reduce the sensitivity of mosquitoes to transfluthrin's repellent effects [[3]](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400042/) [[4]](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266078/), there are suggestions that *Kdr* mutations may not confer resistance to Transfluthrin and other poly-fluorinated pyrethroids, to the same degree as typical pyrethroids. A study showed that *Kdr* mutations in *Aedes aegypti* lead to lower levels of resistance to transfluthrin than with other pyrethroids [[5]](https://www.sciencedirect.com/science/article/pii/S0048357513001478), whilst other research has shown that House-fly *Super-Kdr* does not confer resistance to transfluthrin at all, potentially due to its shorter length [[6]](https://pubmed.ncbi.nlm.nih.gov/26691197/). 

It has even been hypothesised that vapour-phase pyrethroids may bypass cuticular resistance, via direct entry to the nervous system through insect spiracles [[7]](https://link.springer.com/article/10.1007/s13355-016-0443-2). Together, the above factors result in low resistance ratios for transfluthrin when compared with standard pyrethroids [[8]](https://parasitesandvectors.biomedcentral.com/articles/10.1186/s13071-021-04997-8#Sec7), something we have also found with a range of pyrethroid-resistant mosquito strains at the School of Tropical Medicine (unpublished). 

#### Spatial repellent mixtures?

If spatial repellents are shown to be an effective tool for vector control, it will be important to raise discussions on how to maintain and increase the longevity of these products. Whilst writing this, I saw a study which found that transfluthrin does not activate olfactory neurons (like most repellents, such as DEET). Instead, its repellent properties are dependent on sodium channel activation [[9]](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266078/pdf/pntd.0009546.pdf). Interestingly, they also found that minuscule concentrations of transfluthrin synergise the effects of DEET and several other repellents! [[10]](https://www.sciencedirect.com/science/article/pii/S0048357523000524)

This finding suggests that using transfluthrin in a mixture with a non-pyrethroid vapour-phase repellent could be extremely effective, as well as extending the shelf-life of the products themselves. Another recent study identified repellent compounds with greater activity than the gold-standard DEET, and which have similar vapour pressures to transfluthrin [[11]](https://www.sciencedirect.com/science/article/pii/S0048357518303900) which could be ideal within such a mixture.

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In 2023, we find ourselves in desperate need of novel vector control tools. Let's pray that spatial repellents can play an important role in reducing the burden of Malaria. 


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My favourite polyfluorinated pyrethroid