# Plasmid-Bacteria Coevolution Promotes the Spread of Antibiotic Resistance

> **NIH NIH R01** · UNIVERSITY OF IDAHO · 2021 · $372,076

## Abstract

PROJECT SUMMARY/ABSTRACT
Many leading human health organizations such as the World Health Organization and the Centers for Disease
Control and Prevention (CDC) have declared that the increased prevalence of bacterial pathogens that are
resistant to multiple antibiotics is a significant human health crisis. The emergence of these multi-drug resistant
(MDR) pathogens is largely due to the sharing of resistance genes by plasmid mediated horizontal gene
transfer. Bacterial plasmids are mobile genetic elements that can confer resistance to a variety of antibiotics,
including those that are considered to be “drugs of last resort”. Our long-term goal is to aid the development
of strategies that can slow the spread of antibiotic resistance by gaining insight into the co-evolutionary
processes that allow bacteria to improve the persistence of newly acquired MDR plasmids. Newly acquired
resistance plasmids often do not persist in the absence of antibiotics, but we and others have shown that
single mutations in the bacterial host, the plasmid, or both can rapidly improve this persistence. We and others
also identified critical mutations in chromosomally encoded accessory helicases. Plasmid-helicase interactions
in bacteria may therefore be key to the ability of bacterial pathogens to retain newly acquired MDR plasmids.
Unfortunately, the molecular mechanisms that explain the positive effects of these mutations on plasmid
persistence are unknown. Importantly, we also showed for the first time that these mutations pre-adapt the
bacteria to other MDR plasmids that they acquire later in time, leading to their enhanced persistence (referred
to as increased plasmid permissiveness). This suggests that bacteria with increased permissiveness can serve
as stable repositories for multiple MDR plasmids, eventually generating strains with an expanded arsenal of
resistance genes. This possibility has never been tested. Using molecular techniques, experimental evolution
and mathematical modeling, we propose to test the following hypotheses: (i) chromosomal mutations can pre-
adapt bacteria to other plasmids, leading to greater plasmid permissiveness; (ii) plasmid permissiveness can
expand the spectrum of antibiotic resistance traits within a bacterial species; and (iii) accessory helicases are
linked to the persistence of newly acquired MDR plasmids across a wide spectrum of bacterial pathogens. This
will be done through achieving the following Specific Aims: (1) Test the generality of (i) increased plasmid
permissiveness after host/plasmid coevolution, and (ii) helicase mutations as a mechanism of host
adaptation to novel MDR plasmids.; (2) determine the effects of plasmid persistence and
permissiveness on the emergence of expanded drug resistance; (3) determine the molecular
mechanism of plasmid cost amelioration resulting from mutations in accessory helicases. If our
hypotheses are supported by our data, mutations that stabilize one plasmid could lead to improved persi...

## Key facts

- **NIH application ID:** 10142345
- **Project number:** 5R01AI084918-09
- **Recipient organization:** UNIVERSITY OF IDAHO
- **Principal Investigator:** Eva M. Top
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,076
- **Award type:** 5
- **Project period:** 2010-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142345

## Citation

> US National Institutes of Health, RePORTER application 10142345, Plasmid-Bacteria Coevolution Promotes the Spread of Antibiotic Resistance (5R01AI084918-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142345. Licensed CC0.

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