Dataset Information

Nontoxic antimicrobials that evade drug resistance.

ABSTRACT: Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report markedly less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and they bind their target (the fungal sterol ergosterol) with far greater selectivity than AmB. Hence, they are less toxic and far more effective in a mouse model of systemic candidiasis. To our surprise, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB. Thus, highly selective cytocidal action and the evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies.

SUBMITTER: Davis SA

PROVIDER: S-EPMC4472574 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Nontoxic antimicrobials that evade drug resistance.

Davis Stephen A SA Vincent Benjamin M BM Endo Matthew M MM Whitesell Luke L Marchillo Karen K Andes David R DR Lindquist Susan S Burke Martin D MD

Nature chemical biology 20150601 7

Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report markedly less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and they bind their target (the fun ...[more]

PMID: 26030729

Similar Datasets

Project description:IntroductionPrivate sector drug shops are an important source of medicines in Tanzania. In 2003, the government introduced the accredited drug dispensing outlet (ADDO) program to improve access to good-quality medicines in rural and peri-urban areas that have frequent drug shortages in public health facilities and few or no registered pharmacies. However, increasing access may also contribute to antimicrobial resistance (AMR) due to the potential overuse and misuse of drugs.MethodsWe conducted a cross-sectional household survey in four regions in mainland Tanzaniato characterize consumer care-seeking habits and medicines use and to determine the extent to which members of the community are knowledgeable about antimicrobials and AMR. Within the regions, we applied a multistage cluster sampling design, cascading from districts, wards, and villages to households. Multivariate logistic analysis was done to determine variables influencing knowledge of antimicrobials and AMR, while controlling for confounding factors. Variables included age, occupation, level of education, membership in an insurance scheme, and wealth status.Results and discussionWe revealed that communities in four Tanzanian regions have low levels of knowledge of the concepts of antimicrobials and their use and AMR. Level of public understanding rose with wealth status and education. Only one-third of 1,200 respondents (33.6%) had ever heard of a medicine called an antimicrobial, and 5-15% could name at least one antimicrobial spontaneously. Some thought other medicines, such as paracetamol were antimicrobial (7.5%). People were equally likely to agree that pneumonia should be treated with an antimicrobial (21.4%) as well as common cold (28.4%). Understanding of AMR risks was better, particularly related to HIV and AIDS (32.2%) and malaria (38.6%)-most likely due to information campaigns focused on those two diseases. The level of knowledge decreased the further away respondents lived from an ADDO (p = 0.0001) and where ADDO density was lower (p = 0.001), which supports the use of ADDO dispensers as sources of community information and change agents for more appropriate medicine use.ConclusionLack of knowledge about antimicrobials and AMR in Tanzanian communities needs to be addressed through multi-pronged strategies that focus on prescribers and the public-especially those who are poorer and less educated.

Dataset Information

Nontoxic antimicrobials that evade drug resistance.

Publications

Nontoxic antimicrobials that evade drug resistance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets