Are current antibacterial treatments resulting in the evolution of more virulent multidrug resistant bacteria?

By Rodolfo Garcia-Contreras and Jesús Guillermo Jiménez-Cortés

Backed by Hans Westerhoff, Christina Kuttler, Rafael F.Font, Meike Wortel, Bertha Gonzalez Pedrajo, Johan Van Heerden, Mohammad Faisal Haider, Amy Collette, Eric D. Walters, and WEEMING

Universidad Nacional Autónoma de México

Mexico

DOI: 10.18258/10486

$2,044

Raised of $2,018 Goal

101%

Funded on 5/29/18

Successfully Funded

$2,044
pledged
101%
funded
Funded
on 5/29/18

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About This Project

Each year in the U.S. 23,000 people die as a direct result of antibiotic resistant infections. I hypothesize that by combining classical antibiotics, quorum sensing, and virulence inhibitors we can increase the virulence of multidrug resistant Pseudomonas aeriginosa. The results of this study simulate the evolution of multidrug resistant bacteria predicting the worst case scenarios, so we can be better prepared to fight these infections in the future.

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What is the context of this research?

The most common strategy for combatting multidrug resistant bacterial infections is by using multiple antibiotics in combination to attempt to overcome the resistance. Sometimes this strategy works, but when it doesn't this may introduce more virulent strains of bacteria. In 2012, we demonstrated that resistance against quorum sensing inhibitors,specifically C-30 furanone, can be engineered. This publication led us to evaluate the possible effects of a combination of antibiotic treatment and anti quorum sensing treatments on bacterial virulence.

What is the significance of this project?

Do therapies designed to kill multidrug resistant bacteria actually make these bacteria more deadly? This is the question we are asking. For our study, we will use a worm infection model to test our hypothesis. If our hypothesis is supported our medical system needs to rethink how we treat multidrug resistant bacteria. In the clinic we medical professionals use a combination of antibiotics to treat multidrug resistant bacteria without considering the consequences. If our hypothesis is supported the treatments we administer today in the hospital may be encouraging the evolution of even more virulent bacteria. The results of this study will be shared widely with the scientific community through a publication.

What are the goals of the project?

Our goal is to determine how a multi-drug treatment and the virulence inhibitor C-30, separately and in combination, affect the survival and expression of virulence factors of multidrug resistant Pseudomonas aeriginosa. To test our hypothesis we will start evaluating the effect of several antibiotics and C-30 on the survival and the expression of quorum sensing dependent virulence factors (exoproteases, phenazines, biofilm, swarming, etc.) of P. aeruginosa. We will also test this on PA14 and mutants that overexpress the MexAB-OmpR pump and mutants without this pump. We will also run the same experiments on another common bacteria Galleria mellonella. The results will of this study will be published in a peer-reviewed scientific journal.

Budget

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We need to buy diverse consumables for the medium preparation including rich medium like LB (yeast extract, tryptone and NaCl) and specific minimal medium with special carbon sources such as casein or adenosine (which metabolism depend on QS), in addition we need to buy several antibiotics (substrates for the efflux pump), reagents for HPLC, and QS inhibitors.

In order to determine the production of QS dependent virulence factors we need to buy substrates for the exoproteases Elastase and Collagenase, reagents to determine the productions of siderophores and phenzines, rhamnolipids, alginate and other exopolysaccharides, etc. In addition we need to perform type III secretion systems assays (this system is negatively controlled by QS).

To evaluate the virulence of the different strains with and without the antibiotics we need budget to buy Galleria mellonella larvae and to cultivate them.

Endorsed by

Understanding the molecular basis of how does a bacteria acquire resistance to antibiotics and how can we overcome such mechanisms in order to combat them is a critical aspect we need to explore in order to kill them. This is a very relevant project that could greatly impact on the current combined efforts worldwide to successfully eliminate MDR bacterias.

Paula Licona

Assistant profesor

UNAM

ESKAPE which are critical resistant bacteria decided by WHO should be a big issue we have to overcome; therefore, the project proposed is absolutely important and understanding the mechanism of making resistance will address the adequate solution for the issue. In the future, the number of dead people by the bacterial infection with resistant bacteria will correspond to that by cancer; hence, the research proposed should be absolutely performed.

Toshinari Maeda

Associate Professor

Kyushu Institute of Technology

This is a highly relevant and novel project in the field of the ever growing problem of pathogenic bacteria becoming multidrug resistant. Rodolfo worked in our laboratory in Amsterdam for 2.5 years and I got to know him as a dedicated, clever, reliable and hard-working researcher. He made impressive progress as a scientist; he established a firm record of publications on the relation between quorum sensing and antibiotic resistance. All in all, I am convinced that he is highly qualified for the research proposed in this project.

Fred C. Boogerd

Assistant Pofessor

VU University Amsterdam

Project Timeline

1) Determination of exoproteases, pyocyanin, swarming, biofilm, TTSS, etc., efflux (antibiotics and C-30) of PA14 strain and mutants mexR, nalC and mexA and in 5 clinical MDR strains.

2) Test the effect of C-30 and antibiotics on the expression of the virulence factors.

3) Test the effect of C-30 and antibiotics on the survival of infected G. mellonella.

4) Manuscript writing.

Apr 04, 2018

Project Launched

May 01, 2018

Strain characterization

Jul 01, 2018

Determination of the in vitro effects

Sep 01, 2018

Determination of the in vivo effects

Oct 01, 2018

Manuscript preparation

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Meet the Team

Rodolfo Garcia-Contreras

Associate Professor

Affiliates

UNAM (Microbiology and Parasitology Department, Medicine Faculty)

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Jesús Guillermo Jiménez-Cortés

Team Bio

Our team includes 2 postdoctoral researchers (one ecologist and one biochemist/molecular biologist) and several undergraduate and graduate students, hence is a multidisciplinary team including medical doctors, computer scientists, chemical engineers, chemists, biomedical scientists, etc. In addition we have several national and international collaborators.

Rodolfo Garcia-Contreras

I am an associate professor at UNAM (since 2014), previously at INCICH. I obtained my Ph.D. In 2005 at UNAM working with photosynthetic bacteria.

I made two postdoctoral stays, first at Texas A&M University with Thomas K. Wood (bacterial biofilms) and then at the VU Amsterdam with Hans Westerhoff (E. coli systems biology). Currently I study of the resistance of P. aeruginosa against new antimicrobials, the role of QS in stress tolerance, and drug repurposing for finding antimicrobial activities in drugs currently used for other clinical purposes.

I am the author of 39 publications (15 as corresponding author), and have 2 master and 2 Ph.D. students at my charge as well as several interchange students from Japan and Colombia.

in addition I have a nice dog.