Evolution of β-lactamase-mediated Cefiderocol Resistance

Overview

Journal J Antimicrob Chemother

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2022 Jul 11

PMID 35815680

Authors

Christopher Frohlich

Vidar Sorum

Nobuhiko Tokuriki

Pal Jarle Johnsen

Orjan Samuelsen

Affiliations

Soon will be listed here.

Abstract

Background: Cefiderocol is a novel siderophore β-lactam with improved hydrolytic stability toward β-lactamases, including carbapenemases, achieved by combining structural moieties of two clinically efficient cephalosporins, ceftazidime and cefepime. Consequently, cefiderocol represents a treatment alternative for infections caused by MDR Gram-negatives.

Objectives: To study the role of cefiderocol on resistance development and on the evolution of β-lactamases from all Ambler classes, including KPC-2, CTX-M-15, NDM-1, CMY-2 and OXA-48.

Methods: Directed evolution, using error-prone PCR followed by selective plating, was utilized to investigate how the production and the evolution of different β-lactamases cause changes in cefiderocol susceptibility determined using microbroth dilution assays (MIC and IC50).

Results: We found that the expression of blaOXA-48 did not affect cefiderocol susceptibility. On the contrary, the expression of blaKPC-2, blaCMY-2, blaCTX-M-15 and blaNDM-1 substantially reduced cefiderocol susceptibility by 4-, 16-, 8- and 32-fold, respectively. Further, directed evolution on these enzymes showed that, with the acquisition of only 1-2 non-synonymous mutations, all β-lactamases were evolvable to further cefiderocol resistance by 2- (NDM-1, CTX-M-15), 4- (CMY-2), 8- (OXA-48) and 16-fold (KPC-2). Cefiderocol resistance development was often associated with collateral susceptibility changes including increased resistance to ceftazidime and ceftazidime/avibactam as well as functional trade-offs against different β-lactam drugs.

Conclusions: The expression of contemporary β-lactamase genes can potentially contribute to cefiderocol resistance development and the acquisition of mutations in these genes results in enzymes adapting to increasing cefiderocol concentrations. Resistance development caused clinically important cross-resistance, especially against ceftazidime and ceftazidime/avibactam.

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References

Malik S, Kaminski M, Landman D, Quale J . Cefiderocol Resistance in Acinetobacter baumannii: Roles of β-Lactamases, Siderophore Receptors, and Penicillin Binding Protein 3. Antimicrob Agents Chemother. 2020; 64(11). PMC: 7577126. DOI: 10.1128/AAC.01221-20. View

Tiseo G, Falcone M, Leonildi A, Giordano C, Barnini S, Arcari G . Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-, Cefiderocol-Resistant ST-512 -Producing KPC-31, a D179Y Variant of KPC-3. Open Forum Infect Dis. 2021; 8(6):ofab141. PMC: 8233566. DOI: 10.1093/ofid/ofab141. View

Baquero F, Negri M, Morosini M, Blazquez J . Antibiotic-selective environments. Clin Infect Dis. 1998; 27 Suppl 1:S5-11. DOI: 10.1086/514916. View

Bianco G, Boattini M, Comini S, Iannaccone M, Bondi A, Cavallo R . In vitro activity of cefiderocol against ceftazidime-avibactam susceptible and resistant KPC-producing Enterobacterales: cross-resistance and synergistic effects. Eur J Clin Microbiol Infect Dis. 2021; 41(1):63-70. DOI: 10.1007/s10096-021-04341-z. View

Baquero F, Negri M . Selective compartments for resistant microorganisms in antibiotic gradients. Bioessays. 1997; 19(8):731-6. DOI: 10.1002/bies.950190814. View

Mushtaq S, Sadouki Z, Vickers A, Livermore D, Woodford N . Activity of Cefiderocol, a Siderophore Cephalosporin, against Multidrug-Resistant Gram-Negative Bacteria. Antimicrob Agents Chemother. 2020; 64(12). PMC: 7674041. DOI: 10.1128/AAC.01582-20. View

Nurjadi D, Kocer K, Chanthalangsy Q, Klein S, Heeg K, Boutin S . New Delhi Metallo-Beta-Lactamase Facilitates the Emergence of Cefiderocol Resistance in Enterobacter cloacae. Antimicrob Agents Chemother. 2021; 66(2):e0201121. PMC: 8846454. DOI: 10.1128/AAC.02011-21. View

Baquero F, Negri M, Morosini M, Blazquez J . Selection of very small differences in bacterial evolution. Int Microbiol. 2000; 1(4):295-300. View

Dona V, Scheidegger M, Pires J, Furrer H, Atkinson A, Babouee Flury B . Gradual Evolution of Cefepime Resistance in an ST131 Strain Expressing a Plasmid-Encoded CMY-2 β-Lactamase. Front Microbiol. 2019; 10:1311. PMC: 6581752. DOI: 10.3389/fmicb.2019.01311. View

10.

Simner P, Mostafa H, Bergman Y, Ante M, Tekle T, Adebayo A . Progressive Development of Cefiderocol Resistance in Escherichia coli During Therapy is Associated With an Increase in blaNDM-5 Copy Number and Gene Expression. Clin Infect Dis. 2021; 75(1):47-54. PMC: 9402677. DOI: 10.1093/cid/ciab888. View

11.

Pitout J, Peirano G, Kock M, Strydom K, Matsumura Y . The Global Ascendency of OXA-48-Type Carbapenemases. Clin Microbiol Rev. 2019; 33(1). PMC: 6860007. DOI: 10.1128/CMR.00102-19. View

12.

Tacao M, Correia A, Henriques I . Low Prevalence of Carbapenem-Resistant Bacteria in River Water: Resistance Is Mostly Related to Intrinsic Mechanisms. Microb Drug Resist. 2015; 21(5):497-506. DOI: 10.1089/mdr.2015.0072. View

13.

Stojanoski V, Hu L, Sankaran B, Wang F, Tao P, Prasad B . Mechanistic Basis of OXA-48-like β-Lactamases' Hydrolysis of Carbapenems. ACS Infect Dis. 2021; 7(2):445-460. PMC: 8571991. DOI: 10.1021/acsinfecdis.0c00798. View

14.

Robert X, Gouet P . Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 2014; 42(Web Server issue):W320-4. PMC: 4086106. DOI: 10.1093/nar/gku316. View

15.

Frohlich C, Sorum V, Thomassen A, Johnsen P, Leiros H, Samuelsen O . OXA-48-Mediated Ceftazidime-Avibactam Resistance Is Associated with Evolutionary Trade-Offs. mSphere. 2019; 4(2). PMC: 6437269. DOI: 10.1128/mSphere.00024-19. View

16.

Kawai A, McElheny C, Iovleva A, Kline E, Sluis-Cremer N, Shields R . Structural Basis of Reduced Susceptibility to Ceftazidime-Avibactam and Cefiderocol in Due to AmpC R2 Loop Deletion. Antimicrob Agents Chemother. 2020; 64(7). PMC: 7318025. DOI: 10.1128/AAC.00198-20. View

17.

Di Luca M, Sorum V, Starikova I, Kloos J, Hulter N, Naseer U . Low biological cost of carbapenemase-encoding plasmids following transfer from Klebsiella pneumoniae to Escherichia coli. J Antimicrob Chemother. 2016; 72(1):85-89. DOI: 10.1093/jac/dkw350. View

18.

Ito-Horiyama T, Ishii Y, Ito A, Sato T, Nakamura R, Fukuhara N . Stability of Novel Siderophore Cephalosporin S-649266 against Clinically Relevant Carbapenemases. Antimicrob Agents Chemother. 2016; 60(7):4384-6. PMC: 4914688. DOI: 10.1128/AAC.03098-15. View

19.

Poirel L, Sadek M, Kusaksizoglu A, Nordmann P . Co-resistance to ceftazidime-avibactam and cefiderocol in clinical isolates producing KPC variants. Eur J Clin Microbiol Infect Dis. 2022; 41(4):677-680. DOI: 10.1007/s10096-021-04397-x. View

20.

Jensen P, Hammer K . Artificial promoters for metabolic optimization. Biotechnol Bioeng. 1999; 58(2-3):191-5. View