Tracking the
            <i>in vivo</i>
            evolution of multidrug resistance in
            <i>Staphylococcus aureus</i>
            by whole-genome sequencing

Mwangi, Michael M.; Wu, Shun‐Fan; Zhou, Yanjiao; Sieradzki, Krzysztof; Lencastre, Hermı́nia de; Richardson, Paul; Bruce, David; Rubin, Edward M.; Myers, Eugene W.; Siggia, Eric D.; Tomasz, Alexander

doi:10.1073/pnas.0609839104

Cited by 495 publications

(443 citation statements)

References 48 publications

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“…Mutations leading to resistance including agr, other polymorphisms and the expression of these, are another key area for ongoing research [42][43][44][45]. Until these mechanisms are more fully understood, current practice will consist of somewhat unsatisfactory phenotypic methods of resistance detection before molecular methods of resistance detection or certainty of susceptibility become available [28].…”

Section: Heteroresistancementioning

confidence: 99%

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

Edwards

Andini

Esposito

et al. 2014

Journal of Global Antimicrobial Resistance

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Section: Heteroresistancementioning

confidence: 99%

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

Edwards

Andini

Esposito

et al. 2014

Journal of Global Antimicrobial Resistance

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“…For example, 19 non-synonymous point mutations and 10 indels accumulated over 12 weeks of (unsuccessful) antibiotic therapy of a patient suffering from Staphylococcus aureus endocarditis, as did six synonymous point mutations [3]. Many of these mutations were in genes that are linked to antibiotic resistance or encode transcriptional global regulators.…”

Section: Darwinian Selection During Adaptationmentioning

confidence: 99%

Insights from genomic comparisons of genetically monomorphic bacterial pathogens

Achtman

2012

Phil. Trans. R. Soc. B

116

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Some of the most deadly bacterial diseases, including leprosy, anthrax and plague, are caused by bacterial lineages with extremely low levels of genetic diversity, the so-called 'genetically monomorphic bacteria'. It has only become possible to analyse the population genetics of such bacteria since the recent advent of high-throughput comparative genomics. The genomes of genetically monomorphic lineages contain very few polymorphic sites, which often reflect unambiguous clonal genealogies. Some genetically monomorphic lineages have evolved in the last decades, e.g. antibiotic-resistant Staphylococcus aureus, whereas others have evolved over several millennia, e.g. the cause of plague, Yersinia pestis. Based on recent results, it is now possible to reconstruct the sources and the history of pandemic waves of plague by a combined analysis of phylogeographic signals in Y. pestis plus polymorphisms found in ancient DNA. Different from historical accounts based exclusively on human disease, Y. pestis evolved in China, or the vicinity, and has spread globally on multiple occasions. These routes of transmission can be reconstructed from the genealogy, most precisely for the most recent pandemic that was spread from Hong Kong in multiple independent waves in 1894.

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“…Tumors in particular are thought to contain numerous resistant variants by the time neoplasms are typically discovered [22]. The above five mechanisms are largely inferred from in vitro experiments; their detailed roles in treatment failures are largely unknown (e.g., [23]). …”

Section: Dca Escapementioning

confidence: 99%

Six wedges to curing disease

Hochberg

2017

Preprint

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Abstract.One of the great challenges in ecology and evolutionary biology is to explain disease, whether caused by infectious agents such as parasites and pathogens, or by the deterioration or transformation of cellular behavior and function, a prime example of the latter being cancer. Decades of observation and research suggest that successfully treating disease requires insights into how the environment mediates the interactions between disease causing agents (DCAs) and diseased individuals. A major finding is that single factor, targeted therapies are not only likely to fail in controlling or eradicating many DCAs, but are also likely to select for resistance, reducing options for subsequent treatment attempts, and in cases of infectious DCAs, rendering therapeutic agents (e.g., antibiotics) obsolete.I argue that meeting the growing challenge of treating disease in agriculture and animal husbandry, in protected and domesticated species, wildlife, and in the human population will require a fundamental understanding of ecological interactions at sites of infection or disease. I discuss different ways in which components of such disease ecosystems mediate DCA and therapeutic dynamics and resistance evolution, and derive a very simple mathematical criterion for therapeutic success. I then touch on how fundamental insights as revealed by the processes of evolutionary rescue and competitive release can help understand why therapies succeed or fail. Finally, I present six "wedges" that can each contribute alone, or as part of multi-pronged approaches to successfully treating disease. The Magic BulletDespite remarkable progress in prevention and treatment, the impacts of diseases in agriculture and animal husbandry, and on protected and domesticated species, wildlife, and human health are likely to intensify into the 21 st century. Humans in particular are increasingly in contact with each other and with wildlife, treated with drug regimens that select for resistance, and adopt life-styles or are exposed to environments that render them more susceptible to infectious diseases and more likely to get cellular diseases such as cancers.For many clinicians the Holy Grail is to discover the Ehrlichian "Magic Bullet"-a drug that will target the disease-causing agents (DCAs) and cure disease. Intuitively, the most effective way to reduce DCAs is to "hit hard and fast". That is, more drug means more kill within the tolerance limits of the patient. Rapid administration of the drug means forestalling further DCA growth and associated symptoms, but also reducing the probability of the appearance of resistant mutant strains. Despite decades of research on pest and disease control (much of it with an ecological basis) this approach and the many alternatives described below remain highly controversial (e.g., [1]).The Magic Bullet may be shortsighted for another reason. What will cure most patients may not be optimal for the general population in which resistant variants may emerge and spread 1 . This problem is in many ways similar...

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Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing

Cited by 495 publications

References 48 publications

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

Insights from genomic comparisons of genetically monomorphic bacterial pathogens

Six wedges to curing disease

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