John Osei Sekyere
Thamarai Schneiders
Piotr Majewski- 1Medical Diagnostic Laboratories, Institute of Biomarker Research, Department of Clinical Development, Genesis Biotechnology Group, Hamilton Township, NJ, United States
- 2Department of Dermatology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
- 3Center for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom
- 4Department of Microbiological Diagnostics and Infectious Immunology, Medical University of Białystok, Białystok, Poland
Editorial on the Research Topic
Molecular mechanisms of resistance to “last resort” antimicrobials in Enterobacterales
The use and misuse of antibiotics in veterinary and human medicine, agriculture, and aquaculture are selecting resistance genes in different bacterial species (Osei Sekyere, 2016; Tang et al., 2017) Owing to this selection pressure, bacterial strains with resistance to several, if not all antibiotics in current use (also known as pandrug resistance), are emerging (Manageiro et al., 2012; Guducuoglu et al., 2018; Kopotsa et al., 2020; Osei Sekyere and Reta, 2020). Further, more and more of these resistance genes are escaping the chromosome unto mobile genetic elements (MGEs) i.e., plasmids, transposons, integrons, and integrative conjugative elements, under antibiotic pressure, enabling erstwhile susceptible strains to horizontally obtain these mobile resistance genes (Pedersen et al., 2018; Kopotsa et al., 2019, 2020). This worrying trend presents a great challenge for human medicine as recommended antibiotics become ineffective against common bacterial pathogens (Manageiro et al., 2012; Guducuoglu et al., 2018). The emergence of carbapenem, colistin, and tigecycline resistance is a perfect example of this phenomenon of antibiotic resistance evolution (Osei Sekyere et al., 2016).
Specifically, the use of extended-spectrum penicillins and cephalosporins to treat penicillin-resistant infections, mediated by AmpCs, blaOXA, blaSHV and blaTEM, led to the selection and evolution of blaCTX-M and plasmid-mediated AmpCs, blaSHV and blaTEM (Bush, 2018). With the proliferation of the penicillinases and cephalosporinases, particularly through IncF plasmids and other MGEs, carbapenems were introduced to treat infections that were insensitive to the penicillins and cephalosporins, leading to the evolution/emergence and rapid dissemination of the carbapenemases: blaKPC, blaGES, blaSME, blaIMP, blaOXA-48-likeblaVIM, blaSPM, and blaNDM (Osei Sekyere et al., 2015; Bush, 2018; Ragheb et al., 2022). Expectedly, the carbapenemases made carbapenems, which used to be the reserved or last-resort antibiotic, ineffective against infections caused by carbapenemase-producing pathogens. Clinicians therefore resorted to colistin and tigecycline as additional reserved/last-resort antibiotics to replace or supplement carbapenem therapy in multidrug-resistant infections (Osei Sekyere et al., 2016).
In Tembisa, South Africa, an outbreak of NDM and OXA-48-like carbapenemase-producing Enterobacterales (Klebsiella pneumoniae, Enterobacter cloacae, and Escherichia coli) claimed 10 infant lives between December 2019 and March 2020 (Osei Sekyere et al.). These pathogens harbored blaOXA-48-like and blaNDM on plasmids and composite transposons, facilitating the spread of the carbapenemases across different species. Similarly in Bahrain (Shahid et al), the same carbapenemases were identified in 24 pandrug-resistant K. pneumoniae, with blaNDM being found on ISAba125. As observed in the South African strains (Osei Sekyere et al.), these 24 strains were resistant to most antibiotics including colistin (75%), ceftolozone-tazobactam (100%), piperacillin-tazobactam (96%), meropenem (92%) and intermediate resistant to tigecycline (44%).
Ceftazidime-avibactam resistance, a last-resort antibiotic reserved for multidrug-resistant Pseudomonas aeruginosa, was identified by Flury et al. in Switzerland in imipenem-resistant P. aeruginosa. These strains had truncated or absent OprD genes, derepressed AmpCs, and overexpressed mexAB and blaPER-1. As well, Li et al., isolated Pseudomonas asiatica strains with resistance to tigecycline and carbapenems in a hospital’s sewage in China, suggesting the presence of these strains in the hospital environment. Notably, the P. asiatica strains had multiple resistance genes on novel Tn7389 and Tn7493 transposons on large plasmids (~199, 972 bp) that were transferable to P. aeruginosa (but not to E. coli), albeit with a fitness cost to pathogenicity when tested in a Galleria mellonella infection model.
The clinical effect of these carbapenemases is described by Larcher et al. They assessed the effect of last-resort antibiotics such as ceftazidime-avibactam plus aztreonam, imipenem-cilastatin-relebactam, and cefiderocol (a 5th or 6th-generation cephalosporin approved in 2019) on blaNDM -positive infections in patients hospitalized at a tertiary hospital in Nimes, France. Between 2020–2022, the infection survival rate was 45.4%, clinical failure rate was 30%, microbiological failure rate was 33%, and mortality rate was 23%. These statistics show the clinical difficulty associated with managing carbapenem-resistant infections.
Although colistin resistance is relatively recent, Mmatli et al. showed that it has spread globally, with the use of colistin-growth promoters facilitating its spread among food-producing animals, farm environments, wastewater, and ultimately, in humans. The mcr genes were mainly located on IncH, IncC, IncI, IncX, and IncP plasmids as well as on IS1595. Furthermore, Sato et al. isolated Enterobacterales from 258 companion animals in Japan and found 12 and one colistin-resistant Enterobacter cloacae and K. pneumoniae isolates, respectively. The 12 E. cloacae strains belonged to the same lineage as that of human-associated lineages, suggesting a potential animal-human transmission of these strains. The evolution, genetic environment, diversity and proliferation of mcr and mcr variants were further corroborated by Gaballa et al. who identified 125 putative new mcr-like genes from 69,814 MCR-like proteins present in 256 bacterial genera.
Tigecycline resistance, which is still limited in geographic and species spread, were reviewed by Korczak et al., who found efflux pumps, porins (in the outer membrane), regulators of efflux and porins, and tet genes as major tigecycline resistance mechanisms. Some of these genes were found on plasmids, which can facilitate their quick dissemination across species and wider geographic regions if tigecycline use is not well regulated.
Hence, it is evident from this Research Topic that bacterial strains that are resistant to last-resort antibiotics are being selected and spread globally, resulting in outbreaks and fatal infections. The need for continued genomic surveillance and strict antibiotic stewardship to protect these reserved antibiotics cannot be overemphasized.
Author contributions
JO: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. TS: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing. PM: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing.
Conflict of interest
Author JO was employed by the company Genesis Biotechnology Group.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Bush, K. (2018). Past and present perspectives on β-lactamases. Antimicrob. Agents Chemother. 62, aac.01076–18. doi: 10.1128/AAC.01076-18
Guducuoglu, H., Gursoy, N. C., Yakupogullari, Y., Parlak, M., Karasin, G., Sunnetcioglu, M., et al. (2018). Hospital outbreak of a colistin-resistant, NDM-1- and OXA-48-producing klebsiella pneumoniae: high mortality from pandrug resistance. Microb. Drug Resist. 24, 966–972. doi: 10.1089/mdr.2017.0173
Kopotsa, K., Mbelle, N. M., Osei Sekyere, J. (2020). Epigenomics, genomics, resistome, mobilome, virulome and evolutionary phylogenomics of carbapenem-resistant Klebsiella pneumoniae clinical strains. Microb. Genom. 6 (12), mgen000474. doi: 10.1099/mgen.0.000474
Kopotsa, K., Osei Sekyere, J., Mbelle, N. M. (2019). Plasmid evolution in carbapenemase-producing Enterobacteriaceae: a review. Ann. New 1457, 61–91. doi: 10.1111/nyas.14223
Manageiro, V., Jones-Dias, D., Ferreira, E., Louro, D., Canica, M. (2012). Genetic diversity and clonal evolution of carbapenem-resistant Acinetobacter baumannii isolates from Portugal and the dissemination of ST118. Int. J. Antimicrob. Agents 40, 398–403. doi: 10.1016/j.ijantimicag.2012.06.013
Osei Sekyere, J. (2016). Current state of resistance to antibiotics of last-resort in South Africa: A review from a public health perspective. Front. Public Heal. 4. doi: 10.3389/fpubh.2016.00209
Osei Sekyere, J., Govinden, U., Bester, L. A., Essack, S. Y. (2016). Colistin and tigecycline resistance in carbapenemase-producing gram negative bacteria: emerging resistance mechanisms and detection methods. J. Appl. Microbiol. 121, 601–617. doi: 10.1111/jam.13169
Osei Sekyere, J., Govinden, U., Essack, S. (2015). The molecular epidemiology and genetic environment of carbapenemases detected in Africa. Microb. Drug Resist. 22, 59–68. doi: 10.1089/mdr.2015.0053
Osei Sekyere, J., Reta, M. A. (2020). Genomic and resistance epidemiology of gram-negative bacteria in Africa: a systematic review and phylogenomic analyses from a one health perspective. mSystems 5, msystems.00897–20. doi: 10.1128/mSystems.00897-20
Pedersen, T., Osei Sekyere, J., Govinden, U., Moodley, K., Sivertsen, A., Samuelsen, Ø., et al. (2018). Spread of plasmid-encoded NDM-1 and GES-5 carbapenemases among extensively drug-resistant and pandrug-resistant clinical enterobacteriaceae in Durban, South Africa. Antimicrob. Agents Chemother. 62, e02178–e02117. doi: 10.1128/AAC.02178-17
Ragheb, S. M., Govinden, U., Osei Sekyere, J. (2022). Genetic support of carbapenemases: a One Health systematic review and meta-analysis of current trends in Africa. Ann. N. Y. Acad. Sci., 1509 (1), 1–24. doi: 10.1111/nyas.14703
Tang, K. L., Caffrey, N. P., Nóbrega, D. B., Cork, S. C., Ronksley, P. E., Barkema, H. W., et al. (2017). Restricting the use of antibiotics in food-producing animals and its associations with antibiotic resistance in food-producing animals and human beings: a systematic review and meta-analysis. Lancet Planet. Heal. 1, e316. doi: 10.1016/S2542-5196(17)30141-9
Keywords: colistin, tigecycline, carbapenem, reserved antibiotics, last-resort antibiotics, Enterobacterales
Citation: Osei Sekyere J, Schneiders T and Majewski P (2024) Editorial: Molecular mechanisms of resistance to “last resort” antimicrobials in Enterobacterales. Front. Cell. Infect. Microbiol. 14:1429200. doi: 10.3389/fcimb.2024.1429200
Received: 07 May 2024; Accepted: 16 May 2024;
Published: 30 May 2024.
Edited and Reviewed by:
Mathieu Coureuil, Institut National de la Santé et de la Recherche Médicale (INSERM), FranceCopyright © 2024 Osei Sekyere, Schneiders and Majewski. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: John Osei Sekyere, ai5vc2Vpc2VreWVyZUB1cC5hYy56YQ==; am9zZWlzZWt5ZXJlQG1kbGFiLmNvbQ==; am9kMTQxMzlAZ21haWwuY29t
†ORCID: John Osei Sekyere, orcid.org/0000-0002-9508-984X
Thamarai Schneiders, orcid.org/0000-0002-7758-7925
Piotr Majewski, orcid.org/0000-0002-3097-4581