Enhancing the Efficacy of Chloramphenicol Therapy for <i>Escherichia coli</i> by Targeting the Secondary Resistome
The increasing prevalence of antimicrobial resistance and the limited availability of new antimicrobial agents have created an urgent need for new approaches to combat these issues. One such approach involves reevaluating the use of old antibiotics to ensure their appropriate usage and maximize thei...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/13/1/73 |
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| author | Mosaed Saleh A. Alobaidallah Vanesa García Sandra M. Wellner Line E. Thomsen Ana Herrero-Fresno John Elmerdahl Olsen |
| author_facet | Mosaed Saleh A. Alobaidallah Vanesa García Sandra M. Wellner Line E. Thomsen Ana Herrero-Fresno John Elmerdahl Olsen |
| author_sort | Mosaed Saleh A. Alobaidallah |
| collection | DOAJ |
| description | The increasing prevalence of antimicrobial resistance and the limited availability of new antimicrobial agents have created an urgent need for new approaches to combat these issues. One such approach involves reevaluating the use of old antibiotics to ensure their appropriate usage and maximize their effectiveness, as older antibiotics could help alleviate the burden on newer agents. An example of such an antibiotic is chloramphenicol (CHL), which is rarely used due to its hematological toxicity. In the current study, we employed a previously published transposon mutant library in MG1655/pTF2::<i>bla</i><sub>CTX-M-1</sub>, containing over 315,000 unique transposon insertions, to identify the genetic factors that play an important role during growth in the presence of CHL. The list of conditionally essential genes, collectively referred to as the secondary resistome (SR), included 67 genes. To validate our findings, we conducted gene knockout experiments on six genes: <i>arcA</i>, <i>hfq</i>, <i>acrZ</i>, <i>cls</i>, <i>mdfA</i>, and <i>nlpI</i>. Deleting these genes resulted in increased susceptibility to CHL as demonstrated by MIC estimations and growth experiments, suggesting that targeting the products encoded from these genes may reduce the dose of CHL needed for treatment and hence reduce the toxicity associated with CHL treatment. Thus, the gene products are indicated as targets for antibiotic adjuvants to favor the use of CHL in modern medicine. |
| first_indexed | 2024-03-08T11:07:58Z |
| format | Article |
| id | doaj.art-f079736535d54b39bb42b5ea11025f56 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-08T11:07:58Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-f079736535d54b39bb42b5ea11025f562024-01-26T14:37:23ZengMDPI AGAntibiotics2079-63822024-01-011317310.3390/antibiotics13010073Enhancing the Efficacy of Chloramphenicol Therapy for <i>Escherichia coli</i> by Targeting the Secondary ResistomeMosaed Saleh A. Alobaidallah0Vanesa García1Sandra M. Wellner2Line E. Thomsen3Ana Herrero-Fresno4John Elmerdahl Olsen5Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, DenmarkDepartment of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, DenmarkDepartment of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, DenmarkDepartment of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, DenmarkDepartment of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, DenmarkDepartment of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, DenmarkThe increasing prevalence of antimicrobial resistance and the limited availability of new antimicrobial agents have created an urgent need for new approaches to combat these issues. One such approach involves reevaluating the use of old antibiotics to ensure their appropriate usage and maximize their effectiveness, as older antibiotics could help alleviate the burden on newer agents. An example of such an antibiotic is chloramphenicol (CHL), which is rarely used due to its hematological toxicity. In the current study, we employed a previously published transposon mutant library in MG1655/pTF2::<i>bla</i><sub>CTX-M-1</sub>, containing over 315,000 unique transposon insertions, to identify the genetic factors that play an important role during growth in the presence of CHL. The list of conditionally essential genes, collectively referred to as the secondary resistome (SR), included 67 genes. To validate our findings, we conducted gene knockout experiments on six genes: <i>arcA</i>, <i>hfq</i>, <i>acrZ</i>, <i>cls</i>, <i>mdfA</i>, and <i>nlpI</i>. Deleting these genes resulted in increased susceptibility to CHL as demonstrated by MIC estimations and growth experiments, suggesting that targeting the products encoded from these genes may reduce the dose of CHL needed for treatment and hence reduce the toxicity associated with CHL treatment. Thus, the gene products are indicated as targets for antibiotic adjuvants to favor the use of CHL in modern medicine.https://www.mdpi.com/2079-6382/13/1/73<i>Escherichia coli</i>chloramphenicolmulti-drug-resistant bacteriaextended-spectrum beta-lactamasetransposon-directed insertion site sequencingantibiotic adjuvants |
| spellingShingle | Mosaed Saleh A. Alobaidallah Vanesa García Sandra M. Wellner Line E. Thomsen Ana Herrero-Fresno John Elmerdahl Olsen Enhancing the Efficacy of Chloramphenicol Therapy for <i>Escherichia coli</i> by Targeting the Secondary Resistome Antibiotics <i>Escherichia coli</i> chloramphenicol multi-drug-resistant bacteria extended-spectrum beta-lactamase transposon-directed insertion site sequencing antibiotic adjuvants |
| title | Enhancing the Efficacy of Chloramphenicol Therapy for <i>Escherichia coli</i> by Targeting the Secondary Resistome |
| title_full | Enhancing the Efficacy of Chloramphenicol Therapy for <i>Escherichia coli</i> by Targeting the Secondary Resistome |
| title_fullStr | Enhancing the Efficacy of Chloramphenicol Therapy for <i>Escherichia coli</i> by Targeting the Secondary Resistome |
| title_full_unstemmed | Enhancing the Efficacy of Chloramphenicol Therapy for <i>Escherichia coli</i> by Targeting the Secondary Resistome |
| title_short | Enhancing the Efficacy of Chloramphenicol Therapy for <i>Escherichia coli</i> by Targeting the Secondary Resistome |
| title_sort | enhancing the efficacy of chloramphenicol therapy for i escherichia coli i by targeting the secondary resistome |
| topic | <i>Escherichia coli</i> chloramphenicol multi-drug-resistant bacteria extended-spectrum beta-lactamase transposon-directed insertion site sequencing antibiotic adjuvants |
| url | https://www.mdpi.com/2079-6382/13/1/73 |
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