Unstable Mechanisms of Resistance to Inhibitors of Escherichia coli Lipoprotein Signal Peptidase
| Autor: | Donghong Yan, Keira Garland, Marie-Gabrielle Braun, Yiming Xu, Anand Kumar Katakam, Emily J. Hanan, Yutian Peng, Jing Kang, Meredith Sagolla, Jingyu Diao, Homer Pantua, Cary D. Austin, Cameron L. Noland, Sharookh B. Kapadia, Georgette Castanedo, Zora Modrusan, Min Xu, Susan L. Gloor, Janina Reeder, Elizabeth Skippington, László G. Kömüves, Jeremy Murray |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
globomycin
medicine.drug_class Lipoproteins Antibiotics Population Lpp Biology Lipoprotein signal peptidase medicine.disease_cause Microbiology Coli strain Mice Bacterial Proteins Enterobacteriaceae Virology Drug Resistance Bacterial medicine Escherichia coli Animals Aspartic Acid Endopeptidases Humans Uropathogenic Escherichia coli heteroresistance education Escherichia coli Infections Genetics education.field_of_study lipoprotein Pathogenic bacteria Therapeutics and Prevention Phenotype QR1-502 Anti-Bacterial Agents Mice Inbred C57BL LspA Female Bacterial outer membrane Peptides Research Article |
| Zdroj: | mBio, Vol 11, Iss 5 (2020) mBio |
| ISSN: | 2150-7511 |
| DOI: | 10.1128/mBio.02018-20 |
| Popis: | Despite increasing evidence suggesting that antibiotic heteroresistance can lead to treatment failure, the significance of this phenomena in the clinic is not well understood, because many clinical antibiotic susceptibility testing approaches lack the resolution needed to reliably classify heteroresistant strains. Here we present G0790, a new globomycin analog and potent inhibitor of the Escherichia coli type II signal peptidase LspA. We demonstrate that in addition to previously known mechanisms of resistance to LspA inhibitors, unstable genomic amplifications containing lspA can lead to modest yet biologically significant increases in LspA protein levels that confer a heteroresistance phenotype. Clinical development of antibiotics with novel mechanisms of action to kill pathogenic bacteria is challenging, in part, due to the inevitable emergence of resistance. A phenomenon of potential clinical importance that is broadly overlooked in preclinical development is heteroresistance, an often-unstable phenotype in which subpopulations of bacterial cells show decreased antibiotic susceptibility relative to the dominant population. Here, we describe a new globomycin analog, G0790, with potent activity against the Escherichia coli type II signal peptidase LspA and uncover two novel resistance mechanisms to G0790 in the clinical uropathogenic E. coli strain CFT073. Building on the previous finding that complete deletion of Lpp, the major Gram-negative outer membrane lipoprotein, leads to globomycin resistance, we also find that an unexpectedly modest decrease in Lpp levels mediated by insertion-based disruption of regulatory elements is sufficient to confer G0790 resistance and increase sensitivity to serum killing. In addition, we describe a heteroresistance phenotype mediated by genomic amplifications of lspA that result in increased LspA levels sufficient to overcome inhibition by G0790 in culture. These genomic amplifications are highly unstable and are lost after as few as two subcultures in the absence of G0790, which places amplification-containing resistant strains at high risk of being misclassified as susceptible by routine antimicrobial susceptibility testing. In summary, our study uncovers two vastly different mechanisms of resistance to LspA inhibitors in E. coli and emphasizes the importance of considering the potential impact of unstable and heterogenous phenotypes when developing antibiotics for clinical use. |
| Databáze: | OpenAIRE |
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