Genomic features of in vitro selected mutants of Escherichia coli with decreased susceptibility to tigecycline
ABSTRACT: Objectives: The increase in multidrug-resistant bacteria has reached an alarming rate globally, making it necessary to understand the underlying mechanisms mediating resistance in order to discover new therapeutics. Tigecycline (TGC) is a last-resort antimicrobial agent for the treatment...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Journal of Global Antimicrobial Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213716522001904 |
| _version_ | 1811292910488911872 |
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| author | Mehri Haeili Yalda Shoghi Mohaddeseh Moghimi Arash Ghodousi Maryam Omrani Daniela Maria Cirillo |
| author_facet | Mehri Haeili Yalda Shoghi Mohaddeseh Moghimi Arash Ghodousi Maryam Omrani Daniela Maria Cirillo |
| author_sort | Mehri Haeili |
| collection | DOAJ |
| description | ABSTRACT: Objectives: The increase in multidrug-resistant bacteria has reached an alarming rate globally, making it necessary to understand the underlying mechanisms mediating resistance in order to discover new therapeutics. Tigecycline (TGC) is a last-resort antimicrobial agent for the treatment of serious infections caused by extensively drug-resistant Enterobacteriaceae. Methods: The TGC-resistant Escherichia coli mutants were obtained by exposing three different TGC-susceptible isolates belonging to ST131 (n = 2) and ST405 (n = 1) to increasing concentrations of TGC. The genetic alterations associated with reduced susceptibility to TGC were identified using whole genome sequencing. The fitness cost of TGC resistance acquisition, as well as incidence of cross-resistance, was also investigated. Results: The TGC minimum inhibitory concentrations (MICs) of in vitro selected mutants were elevated 8 to 32 times compared with ancestral strains. Inactivating mutations (frameshift and nonsense) or amino acid substitutions were identified in genes encoding proteins with diverse functions, including AcrAB efflux pump or its regulators (lon and marR), Lipopolysaccharides (LPS) inner core biosynthesis enzymes (waaQ and eptB), ribosomal S9 protein (rpsI), and RNA polymerase β subunit. In most cases (but not all), acquisition of TGC resistance was associated with a fitness cost. While TGC resistance development was associated with cross-resistance to other members of the tetracycline family and chloramphenicol, hypersensitivity to nitrofurantoin was identified among heptose III-less LPS mutants. Conclusion: TGC resistance among the studied mutants was found to be multifactorial with extrusion by efflux transports being the most common mechanism. The LPS inner core biosynthesis pathway, as well as ribosomal S9 protein, could be additional targets for TGC resistance. |
| first_indexed | 2024-04-13T04:53:32Z |
| format | Article |
| id | doaj.art-8527a9a71a17471ea0bb4cf91b976488 |
| institution | Directory Open Access Journal |
| issn | 2213-7165 |
| language | English |
| last_indexed | 2024-04-13T04:53:32Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Global Antimicrobial Resistance |
| spelling | doaj.art-8527a9a71a17471ea0bb4cf91b9764882022-12-22T03:01:35ZengElsevierJournal of Global Antimicrobial Resistance2213-71652022-12-01313237Genomic features of in vitro selected mutants of Escherichia coli with decreased susceptibility to tigecyclineMehri Haeili0Yalda Shoghi1Mohaddeseh Moghimi2Arash Ghodousi3Maryam Omrani4Daniela Maria Cirillo5Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Corresponding authors. Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, 29 Bahman Blvd, Tabriz, East Azerbaijan, Iran.Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, IranDepartment of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, IranVita-Salute San Raffaele University, Milan, Italy; Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, ItalyIRCCS San Raffaele Scientific Institute, Milan, ItalyVita-Salute San Raffaele University, Milan, Italy; Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Corresponding authors. Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, 29 Bahman Blvd, Tabriz, East Azerbaijan, Iran.ABSTRACT: Objectives: The increase in multidrug-resistant bacteria has reached an alarming rate globally, making it necessary to understand the underlying mechanisms mediating resistance in order to discover new therapeutics. Tigecycline (TGC) is a last-resort antimicrobial agent for the treatment of serious infections caused by extensively drug-resistant Enterobacteriaceae. Methods: The TGC-resistant Escherichia coli mutants were obtained by exposing three different TGC-susceptible isolates belonging to ST131 (n = 2) and ST405 (n = 1) to increasing concentrations of TGC. The genetic alterations associated with reduced susceptibility to TGC were identified using whole genome sequencing. The fitness cost of TGC resistance acquisition, as well as incidence of cross-resistance, was also investigated. Results: The TGC minimum inhibitory concentrations (MICs) of in vitro selected mutants were elevated 8 to 32 times compared with ancestral strains. Inactivating mutations (frameshift and nonsense) or amino acid substitutions were identified in genes encoding proteins with diverse functions, including AcrAB efflux pump or its regulators (lon and marR), Lipopolysaccharides (LPS) inner core biosynthesis enzymes (waaQ and eptB), ribosomal S9 protein (rpsI), and RNA polymerase β subunit. In most cases (but not all), acquisition of TGC resistance was associated with a fitness cost. While TGC resistance development was associated with cross-resistance to other members of the tetracycline family and chloramphenicol, hypersensitivity to nitrofurantoin was identified among heptose III-less LPS mutants. Conclusion: TGC resistance among the studied mutants was found to be multifactorial with extrusion by efflux transports being the most common mechanism. The LPS inner core biosynthesis pathway, as well as ribosomal S9 protein, could be additional targets for TGC resistance.http://www.sciencedirect.com/science/article/pii/S2213716522001904Tigecycline resistanceEscherichia coliEfflux pumpsFitness costRibosomal proteinLPS inner core biosynthesis pathway |
| spellingShingle | Mehri Haeili Yalda Shoghi Mohaddeseh Moghimi Arash Ghodousi Maryam Omrani Daniela Maria Cirillo Genomic features of in vitro selected mutants of Escherichia coli with decreased susceptibility to tigecycline Journal of Global Antimicrobial Resistance Tigecycline resistance Escherichia coli Efflux pumps Fitness cost Ribosomal protein LPS inner core biosynthesis pathway |
| title | Genomic features of in vitro selected mutants of Escherichia coli with decreased susceptibility to tigecycline |
| title_full | Genomic features of in vitro selected mutants of Escherichia coli with decreased susceptibility to tigecycline |
| title_fullStr | Genomic features of in vitro selected mutants of Escherichia coli with decreased susceptibility to tigecycline |
| title_full_unstemmed | Genomic features of in vitro selected mutants of Escherichia coli with decreased susceptibility to tigecycline |
| title_short | Genomic features of in vitro selected mutants of Escherichia coli with decreased susceptibility to tigecycline |
| title_sort | genomic features of in vitro selected mutants of escherichia coli with decreased susceptibility to tigecycline |
| topic | Tigecycline resistance Escherichia coli Efflux pumps Fitness cost Ribosomal protein LPS inner core biosynthesis pathway |
| url | http://www.sciencedirect.com/science/article/pii/S2213716522001904 |
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