Skip to main content
Duke University Libraries
DukeSpace Scholarship by Duke Authors
  • Login
  • Ask
  • Menu
  • Login
  • Ask a Librarian
  • Search & Find
  • Using the Library
  • Research Support
  • Course Support
  • Libraries
  • About
View Item 
  •   DukeSpace
  • Theses and Dissertations
  • Duke Dissertations
  • View Item
  •   DukeSpace
  • Theses and Dissertations
  • Duke Dissertations
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

A mechanistic understanding of the postantibiotic effect and treatment strategies

Thumbnail
View / Download
6.9 Mb
Date
2017
Author
Srimani, Jaydeep
Advisor
You, Lingchong
Repository Usage Stats
237
views
632
downloads
Abstract

Although antibiotics have proven to be one of the great achievements of modern medicine, their efficacy has dramatically decreased over the past several decades. This is due, in part, to the rapid pace of natural bacterial evolution, but also to the overuse and misuse of antibiotics in general. This often selects for drug-resistant pathogens, and allows them to flourish in the face of antibiotic treatment. In addition to the emergence of genetic resistance, bacteria often utilize a number of population-level behaviors to survive antibiotic treatment. This is referred to as collective antibiotic tolerance (CAT). Taken together, antibiotic resistance and tolerance have led to the re-emergence of infectious diseases throughout the world. In general, there are two strategies to combat this risk: develop novel antibiotics, and/or use existing drugs more effectively, so as to minimize the chance of resistance emergence. Novel drug development is a time- and resource-intensive process, and pharmaceutical companies are not financially incentivized to develop these types of drugs. Therefore, it is of increasing importance to understand the population dynamics underlying various bacterial survival mechanisms, and exploit this knowledge to design better antibiotic treatment protocols.

My dissertation research focuses on a prevalent phenomenon called the postantibiotic effect (PAE), which refers to the transient suppression of bacterial growth following antibiotic treatment. Although PAE has been empirically observed in a wide variety of antibiotics and microbial species, heretofore there has not been a definitive mechanistic explanation for this pervasive observation.

In this work, I use a combination of high-throughput microfluidic experiments and computational modeling to examine the relationship between dosing parameters and the degree of bacterial inhibition, quantified by population recovery time. I found that recovery time is a function of total antibiotic, regardless of how the dose profile. Moreover, a minimal model of transport and binding kinetics was sufficient to recapture this trend, suggesting a unifying explanation for historical observations of PAE in a variety of contexts. I validated this modeling using both in silico and in vitro perturbation studies.

Moreover, I showed that efflux inhibition, a common strategy in antibiotic treatment, is effective in certain dynamic-dependent situations. This work puts forth a possible mechanism for PAE, which could serve as a clinical aid in selecting effective antibiotic/adjuvant combinations, as well as in designing periodic antibiotic treatments.

Type
Dissertation
Department
Biomedical Engineering
Subject
Biomedical engineering
Antibiotic resistance
Drug dosing
Postantibiotic effect
Systems biology
Permalink
https://hdl.handle.net/10161/14534
Citation
Srimani, Jaydeep (2017). A mechanistic understanding of the postantibiotic effect and treatment strategies. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/14534.
Collections
  • Duke Dissertations
More Info
Show full item record
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

Rights for Collection: Duke Dissertations


Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info

Make Your Work Available Here

How to Deposit

Browse

All of DukeSpaceCommunities & CollectionsAuthorsTitlesTypesBy Issue DateDepartmentsAffiliations of Duke Author(s)SubjectsBy Submit DateThis CollectionAuthorsTitlesTypesBy Issue DateDepartmentsAffiliations of Duke Author(s)SubjectsBy Submit Date

My Account

LoginRegister

Statistics

View Usage Statistics
Duke University Libraries

Contact Us

411 Chapel Drive
Durham, NC 27708
(919) 660-5870
Perkins Library Service Desk

Digital Repositories at Duke

  • Report a problem with the repositories
  • About digital repositories at Duke
  • Accessibility Policy
  • Deaccession and DMCA Takedown Policy

TwitterFacebookYouTubeFlickrInstagramBlogs

Sign Up for Our Newsletter
  • Re-use & Attribution / Privacy
  • Harmful Language Statement
  • Support the Libraries
Duke University