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Chlorfenapyr: An important new tool for combatting insecticide resistance

James W. Austin, PhD, BCEASTMH: Combatting Resistance: New Approaches to Vector Control October 26, 2015

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Chlorfenapyr: Background

N-substituted halogenated pyrrole (CL303630)

Commercialized as Pirate®, Stalker®, Phantom®, Mythic® and will be Sylando® for Public Health

IRAC Group 13 (uncouplers) MoA affects Respiratory Capability Pro-insecticide

Mixed-Function-Oxidases activate molecule…possibly manipulated?

Non-Repellent!

N

F

F

F

O

NCl

Br

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Pyrroles posit some unique attributes:

CFP is pro-uncoupler - ethoxyethyl protecting group is removed by N-dealkylation

No Cross Resistance with other insecticides

Sometimes negative cross resistance observed

Nonspecific MoA and pro-insecticide nature posit low resistance potentials

Not repellent to most targets; Mosquitoes not repelled after 24 h drying

Chlorfenapyr: Background

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+

Outer membrane

Inner membrane

Matrix

Intermembrane space

++

+ ++

Electron Transport Chainuses food energy to drive

protons out of matrix

+ +

++

+

+ +

+

Food + O2

H2O ADP ATPCO2

+ +++ +

+

+ + ++++

+

+

N

F

F

F Cl

Br

N

matrix

+

++ ++

N

F

F

F

O

NCl

Br

Coupled – Protons drive ATP SynthaseUncoupler transports protons – No ATP made

chlorfenapyr

Protons – couple food oxidation to ATP production

Removal of protecting group

allows proton binding

mitochondrion

Protecting

group

ATP SynthaseProton flow drives ATP synthesis

-

Chlorfenapyr: Uncoupling of Mitochondrial Respiration

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Results: Chlorfenapyr molecule has shown least irritant effect against susceptible and resistant strains among all the insecticides tested allowing more landing time to the vector species on the impregnated surfaces to pick-up lethal dose.

Conclusion: Chlorfenapyr could be an ideal insecticide for management of multiple-insecticide-resistance including pyrethroids.

Chlorfenapyr: Non-Repellent Activity

Source: Verma et al. (2015)J Vector Borne Dis 52, March 2015, pp. 99–103

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Confidential 6

Successful Trials Can be difficult to interpret:

Remember, Chlorfenapyr is a physiological toxin….

Physiological state of cohorts influences outcomes (e.g., lab vs wild strains)

Testing modality is THE KEY here – What lab method best captures and supports field/hut studies (e.g., cone vs cylinders, vs

tunnel assays)

Reliance on conventional known paradigms (for testing) is problematic– Diagnostic doses may only be relevant to specific strains and conditions– Following WHOPES guidelines for neurotoxins is inconsistent for MoA– Cone assays, durations of exposure, post exposure recording, higher control mortality owed to

longer post exposure intervals, understanding testing parameters of dual a.i.s in public health, etc.

Chlorfenapyr: Testing considerations

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Source: Yuan (2015) Acta Tropica 143 pp. 13–17

Black et al. (1994) Pest. Biochem. Phys., 50, 115-128

Chlorfenapyr: Testing considerations

anta

go

nis

tic

syn

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isti

c

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% Mortality of Aedes aegypti susceptible 72h after exposure in cone bioassays to 250 mg/m2 chlorfenapyr.at three different temperatures during exposure and holding time.

• Mortality influenced by holding time and temperature in lab bioassays; Field conditions less so• Increased metabolic rates and enhanced monooxygenase activity at higher temperature generally posit greater mortality• Temp effects reduced during scotophase due to elevated circadian rhythm (especially in field)

Chlorfenapyr: Testing considerations

Dose acquisition and uptake

Partitions between living and dead

Quantifying conversion (CL303268)

in vitro metabolism studies

Induction by P450s

LSTM and BASF collaboration

Additional studies were needed:

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Source: Oxborough et al. (2015) Malaria Journal 14:124

Chlorfenapyr: Testing considerations

WHOPES methodology will not capture the real potential of non-neurotoxins well

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10Source: Oxborough et al. (2015) Malaria Journal 14:124

Chlorfenapyr: Testing considerations

Physiological state is absolutely influential for observing the rate of intoxication

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Interceptor G2

Mortality rates of An. gambiae sl collected in experimental huts with treatments

Blood feeding rates of An. gambiae sl collected in experimental huts with treatments

Chlorfenapyr*: Phase II LLIN Trials

Burkina Faso Trials for Interceptor G2 Trials show: 1) Interceptor G2 outperformed positive control nets at this location, 2) Chlorfenapyr killed more wild resistant mosquitoes than standards, and 3) Blood feeding rates were similar for all nets (*mixture nets)

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Chlorfenapyr: conclusions

Chlorfenapyr is a great repurposed tool which can complement existing malaria control programs

Hut trials continue for chlorfenapyr used in LLINs and IRSs

Collaboration with IVCC and other partners continue for optimization of chlorfenapyr’s utility in public health programs

Future studies continue to identify opportunities and clarify limits to chlorfenapyr

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By The Numbers

In 2013:

• 3.3 billion people in nearly 100 countries were at risk of being infected with malaria

• 198 million people contracted malaria globally

• 584,000 people died of malaria

• 90% of deaths caused by malaria were in Africa

• 78% of deaths were among children under the age of five

Sources: http://www.who.int/malaria/publications/ world_malaria_report_2014/en/

Image: BASF chlorfenapyr field trials, IRSSVK7 test site, Bobo-Dioulasso, Burkina Faso 2015.

Malaria

Thank You

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