A framework for assessing the risk of resistance for antimalarials in development

Ding, Xavier C.; Ubben, David; Wells, Timothy NC

doi:10.1186/1475-2875-11-s1-p23

Cited by 6 publications

(9 citation statements)

References 4 publications

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“…Developers of antimicrobial drugs therefore have no regulatory requirement to make an evolutionary assessment of their products. It is encouraging that some have done so voluntarily (Rottman et al., 2010), and that the risk of resistance evolution has been considered a factor in prioritizing funding on antimalarial drugs (Ding et al., ), but such examples are exceptions.…”

Section: The Regulatory Processmentioning

confidence: 99%

The Value of Concept: Lessons from the Evolution of Antibiotic Resistance

Antonovics

2016

Global Policy

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The evolution of resistance to antibiotics in disease causing pathogens is a major world-wide threat to human health. This paper explores why regulatory, funding and institutional structures have inadequately addressed this issue, focusing on data from the US, but emphasizing that these issues are of global scope and applicability. There is an increasing call for serious acceptance of evolutionary biology by the medical community, but the failure to apply evolutionary ideas to the problem of antibiotic resistance continues. These ideas are deceptively simple in their basic formulation, but require sophisticated expertise when it comes to applying them in practice and to human health. The divergent histories of evolutionary biology and medical research have self-referential constituencies in each field. The field of evolutionary biology does not see the applied issues associated with antibiotic resistance as part of its remit. At the biomedical research level, funding for research on evolution of antibiotic resistance is paltry compared to its importance as a health threat, regulatory requirements do not address evolutionary issues, institutional structures dealing with the issue are undeveloped, and there is even avoidance of the word 'evolution' in the context of antibiotic resistance. Current approaches to antibiotic resistance invoke evolutionary principles at a such a naive level that what is put forward are ineffective seat-of-the-pants rules that have no strong theoretical basis and are almost always in desperate need of justification through evidence-based research. Clear solutions exist but their implementation remains problematic. Policy Implications• Regulatory agencies should recognize that pharmaceuticals, such as antibiotics, developed against biological agents that evolve should be regulated very differently from those that are used against systemic diseases.• Evolutionary impact statements, or their equivalent, should accompany all new antimicrobials as part of the licensing process, and should include tests for the presence of resistance evolution. Labelling requirements should accommodate the potential decreasing efficacy of the drugs resulting from evolution in the target pathogen.• Monitoring programs for antibiotic resistance should be greatly extended, made public, and should include nonhospitalized patients as well as nursing homes. Hospital and nursing home certification should require tests for antimicrobial resistance to major pathogens.• Medical research centers should establish departments of evolutionary biology on a par with other basic science departments such as immunology or cell biology. Funding agencies should establish graduate and postdoctoral training grants in evolutionary biology and establish professional certification for competency in evolutionary studies.• Funding agencies should have programs specifically dedicated to antibiotic resistance evolution, on a par with those that address other specific medical conditions. Funding should be directed at methods for mi...

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Section: The Regulatory Processmentioning

confidence: 99%

The Value of Concept: Lessons from the Evolution of Antibiotic Resistance

Antonovics

2016

Global Policy

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“…[4] Thee mergence of parasite resistance against approved drugs has been on the rise over the last decades,and medical concerns have thus increased dramatically.T wo resistant strains Dd2 and K1 carry mutations and an umber of copies for genes [5] encoding for multidrug resistance transporters, resulting in resistances against currently available antimalarial drugs.Notably,Dd2 is resistant to CQ,mefloquine,and the antifolates sulfadoxine,p yrimethamine,a nd cycloguanil, whereas K1 is resistant to CQ and antifolates. [5] In addition, they show different mutations,l eading to an amino acid exchange of at arget enzyme resulting in resistance against antifolates (sulfadoxine,p yrimethamine,c ycloguanil). Compared with chloroquine/drug-sensitive strains (3D7), the fitness and thus the reproduction rate of chloroquine/multidrug-resistant (Dd2 and K1) parasites is slightly impaired by resistance-mediating polymorphisms in putative drug transporters and/or in target enzymes, [6] even without drug pressure.…”

Section: Introductionmentioning

confidence: 99%

Artemisinin–(Iso)quinoline Hybrids by C−H Activation and Click Chemistry: Combating Multidrug‐Resistant Malaria

et al. 2019

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A substantial challenge worldwide is emergent drug resistance in malaria parasites against approved drugs, such as chloroquine (CQ). To address these unsolved CQ resistance issues, only rare examples of artemisinin (ART)‐based hybrids have been reported. Moreover, protein targets of such hybrids have not been identified yet, and the reason for the superior efficacy of these hybrids is still not known. Herein, we report the synthesis of novel ART–isoquinoline and ART–quinoline hybrids showing highly improved potencies against CQ‐resistant and multidrug‐resistant P. falciparum strains (EC50 (Dd2) down to 1.0 nm; EC50 (K1) down to 0.78 nm) compared to CQ (EC50 (Dd2)=165.3 nm; EC50 (K1)=302.8 nm) and strongly suppressing parasitemia in experimental malaria. These new compounds are easily accessible by step‐economic C−H activation and copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC) click reactions. Through chemical proteomics, putatively hybrid‐binding protein targets of the ART‐quinolines were successfully identified in addition to known targets of quinoline and artemisinin alone, suggesting that the hybrids act through multiple modes of action to overcome resistance.

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“…[2] ARTisane nantiopure sesquiterpene lactone,which was first extracted from the Chinese medicinal plant Artemisia annua L. (sweet wormwood) in 1972 by Youyou Tu (Nobel Prize 2015). [4] Thee mergence of parasite resistance against approved drugs has been on the rise over the last decades,and medical concerns have thus increased dramatically.T wo resistant strains Dd2 and K1 carry mutations and an umber of copies for genes [5] encoding for multidrug resistance transporters, resulting in resistances against currently available antimalarial drugs.Notably,Dd2 is resistant to CQ,mefloquine,and the antifolates sulfadoxine,p yrimethamine,a nd cycloguanil, whereas K1 is resistant to CQ and antifolates. Inspired by these traditional and pharmacologically well-established compounds,many derivatives of artemisinin and quinoline have been designed, synthesized, and biologically investigated.…”

Section: Introductionmentioning

confidence: 99%

“…[3] Isoquinolines and quinolines are further privileged scaffolds,u sed clinically as antimalarial and antiviral drugs,f or example,t hrough the different commercial drugs amodiaquine,p aritaprevir, and tafenoquine (Figure 1B). [5] In addition, they show different mutations,l eading to an amino acid exchange of at arget enzyme resulting in resistance against antifolates (sulfadoxine,p yrimethamine,c ycloguanil). [4] Thee mergence of parasite resistance against approved drugs has been on the rise over the last decades,and medical concerns have thus increased dramatically.T wo resistant strains Dd2 and K1 carry mutations and an umber of copies for genes [5] encoding for multidrug resistance transporters, resulting in resistances against currently available antimalarial drugs.Notably,Dd2 is resistant to CQ,mefloquine,and the antifolates sulfadoxine,p yrimethamine,a nd cycloguanil, whereas K1 is resistant to CQ and antifolates.…”

Section: Introductionmentioning

confidence: 99%

Artemisinin–(Iso)quinoline Hybrids by C−H Activation and Click Chemistry: Combating Multidrug‐Resistant Malaria

et al. 2019

View full text Add to dashboard Cite

Asubstantial challenge worldwide is emergent drug resistance in malaria parasites against approved drugs,such as chloroquine (CQ). To address these unsolved CQ resistance issues,only rare examples of artemisinin (ART)-based hybrids have been reported. Moreover,protein targets of such hybrids have not been identified yet, and the reason for the superior efficacy of these hybrids is still not known. Herein, we report the synthesis of novel ART-isoquinoline and ART-quinoline hybrids showing highly improved potencies against CQresistant and multidrug-resistant P. falciparum strains (EC 50 (Dd2) down to 1.0 nm ;E C 50 (K1) down to 0.78 nm) compared to CQ (EC 50 (Dd2) = 165.3 nm ;E C 50 (K1) = 302.8 nm)and strongly suppressing parasitemia in experimental malaria. These new compounds are easily accessible by step-economic C À Hactivation and copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) clickr eactions.T hrough chemical proteomics,putatively hybrid-binding protein targets of the ART-quinolines were successfully identified in addition to knowntargets of quinoline and artemisinin alone,suggesting that the hybrids act through multiple modes of action to overcome resistance.

show abstract

A framework for assessing the risk of resistance for antimalarials in development

Cited by 6 publications

References 4 publications

The Value of Concept: Lessons from the Evolution of Antibiotic Resistance

The Value of Concept: Lessons from the Evolution of Antibiotic Resistance

Artemisinin–(Iso)quinoline Hybrids by C−H Activation and Click Chemistry: Combating Multidrug‐Resistant Malaria

Artemisinin–(Iso)quinoline Hybrids by C−H Activation and Click Chemistry: Combating Multidrug‐Resistant Malaria

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