Plasmodium falciparum HSP90 inhibitors show divergent resistance despite a shared ATP-binding site

Year: 2026

Type: article

Abstract: Drug resistance poses a major challenge across therapeutic areas including malaria, yet factors governing resistance propensity remain poorly understood. We demonstrate that two HSP90 inhibitors targeting the identical ATP-binding site exhibit dramatically different resistance profiles in P. falciparum. Geldanamycin readily selected 10 distinct resistance mutations conferring up to 22-fold resistance, while AUY-922 required 44 weeks to yield a single A41S mutation with only 2-fold resistance. Resistance mutations mapped throughout geldanamycin's binding pocket but localized near the ATP-binding site for AUY-922. Strikingly, A41S enhanced AUY-922 binding affinity via additional hydrogen bonding, yet stronger binding paradoxically correlated with resistance. Conditional HSP90 knockdown increased geldanamycin sensitivity but not AUY-922 activity, indicating distinct target dependencies despite shared binding sites. We propose AUY-922's lower resistance risk reflects engagement of multiple HSP90 family members. These findings demonstrate that resistance risk cannot be predicted from binding site identity alone, informing development of more durable therapeutics.

Source: Cell Reports

DOI: 10.1016/j.celrep.2026.117664

Institutions: University of California San Diego, Broad Institute, Harvard University, Columbia University Irving Medical Center, University of Dundee, Wellcome Centre for Anti-Infectives Research, Wellcome Sanger Institute, Massachusetts Institute of Technology, Scripps Research Institute

Language: English

Topic: Malaria Research and Control

Subfield: Public Health, Environmental and Occupational Health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,620

Funders: Bill and Melinda Gates Foundation, National Institutes of Health, National Institute of Allergy and Infectious Diseases

Awards: University of California San Diego - to discover innovative therapeutics for the potential treatment of malaria impacting disproportionally low and middle income countries, Columbia University - to develop state-of-the-art research platform to accelerate discovery of innovative medicines required for malaria elimination for the benefit of p..., Defining the resistome in P. falciparum: evolution and mechanism, Defining the complex genetic basis of Plasmodium falciparum resistance to artemisinin and quinine and identifying resistance-refractory therapeutics

OpenAlex ID: W7167416628