# THE ORIGIN AND SPREAD OF MOSAIC PLASMIDS ENCODING MULTI-DRUG RESISTANCE(Research Supplement to Promote Diversity)

> **NIH NIH R01** · UNIVERSITY OF IDAHO · 2022 · $81,190

## Abstract

PROJECT SUMMARY/ABSTRACT (of the Awarded Parent Grant)
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...

## Key facts

- **NIH application ID:** 10275435
- **Project number:** 3R01AI084918-10S1
- **Recipient organization:** UNIVERSITY OF IDAHO
- **Principal Investigator:** Eva M. Top
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $81,190
- **Award type:** 3
- **Project period:** 2010-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10275435

## Citation

> US National Institutes of Health, RePORTER application 10275435, THE ORIGIN AND SPREAD OF MOSAIC PLASMIDS ENCODING MULTI-DRUG RESISTANCE(Research Supplement to Promote Diversity) (3R01AI084918-10S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10275435. Licensed CC0.

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