Evolutionary Trajectories of Beta-Lactamase CTX-M-1 Cluster Enzymes: Predicting Antibiotic Resistance
Extended-spectrum beta-lactamases (ESBL) constitute a key antibiotic-resistance mechanism affecting Gram-negative bacteria, and also an excellent model for studying evolution in real time. A shift in the epidemiology of ESBLs is being observed, which is characterized by the explosive diversification and increase in frequency of the CTX-M-type β-lactamases in different settings. This provides a unique opportunity for studying a protein evolutionary radiation by the sequential acquisition of specific mutations enhancing protein efficiency and fitness concomitantly. The existence of driver antibiotic molecules favoring protein divergence has been investigated by combining evolutionary analyses and experimental site-specific mutagenesis. Phylogenetic reconstruction with all the CTX-M variants described so far provided a hypothetical evolutionary scenario showing at least three diversification events. CTX-M-3 was likely the enzyme at the origin of the diversification in the CTX-M-1 cluster, which was coincident with positive selection acting on several amino acid positions. Sixty-three CTX-M-3 derivatives containing all combinations of mutations under positively selected positions were constructed, and their phenotypic efficiency was evaluated. The CTX-M-3 diversification process can only be explained in a complex selective landscape with at least two antibiotics (cefotaxime and ceftazidime), indicating the need to invoke mixtures of selective drivers in order to understand the final evolutionary outcome. Under this hypothesis, we found congruent results between the in silico and in vitro analyses of evolutionary trajectories. Three pathways driving the diversification of CTX-M-3 towards the most complex and efficient variants were identified. Whereas the P167S pathway has limited possibilities of further diversification, the D240G route shows a robust diversification network. In the third route, drift may have played a role in the early stages of CTX-M-3 evolution. Antimicrobial agents should not be considered only as selectors for efficient mechanisms of resistance but also as diversifying agents of the evolutionary trajectories. Different trajectories were identified using a combination of phylogenetic reconstructions and directed mutagenesis analyses, indicating that such an approach might be useful to fulfill the desirable goal of predicting evolutionary trajectories in antimicrobial resistance.
Vyšlo v časopise:
Evolutionary Trajectories of Beta-Lactamase CTX-M-1 Cluster Enzymes: Predicting Antibiotic Resistance. PLoS Pathog 6(1): e32767. doi:10.1371/journal.ppat.1000735
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1000735
Souhrn
Extended-spectrum beta-lactamases (ESBL) constitute a key antibiotic-resistance mechanism affecting Gram-negative bacteria, and also an excellent model for studying evolution in real time. A shift in the epidemiology of ESBLs is being observed, which is characterized by the explosive diversification and increase in frequency of the CTX-M-type β-lactamases in different settings. This provides a unique opportunity for studying a protein evolutionary radiation by the sequential acquisition of specific mutations enhancing protein efficiency and fitness concomitantly. The existence of driver antibiotic molecules favoring protein divergence has been investigated by combining evolutionary analyses and experimental site-specific mutagenesis. Phylogenetic reconstruction with all the CTX-M variants described so far provided a hypothetical evolutionary scenario showing at least three diversification events. CTX-M-3 was likely the enzyme at the origin of the diversification in the CTX-M-1 cluster, which was coincident with positive selection acting on several amino acid positions. Sixty-three CTX-M-3 derivatives containing all combinations of mutations under positively selected positions were constructed, and their phenotypic efficiency was evaluated. The CTX-M-3 diversification process can only be explained in a complex selective landscape with at least two antibiotics (cefotaxime and ceftazidime), indicating the need to invoke mixtures of selective drivers in order to understand the final evolutionary outcome. Under this hypothesis, we found congruent results between the in silico and in vitro analyses of evolutionary trajectories. Three pathways driving the diversification of CTX-M-3 towards the most complex and efficient variants were identified. Whereas the P167S pathway has limited possibilities of further diversification, the D240G route shows a robust diversification network. In the third route, drift may have played a role in the early stages of CTX-M-3 evolution. Antimicrobial agents should not be considered only as selectors for efficient mechanisms of resistance but also as diversifying agents of the evolutionary trajectories. Different trajectories were identified using a combination of phylogenetic reconstructions and directed mutagenesis analyses, indicating that such an approach might be useful to fulfill the desirable goal of predicting evolutionary trajectories in antimicrobial resistance.
Zdroje
1. CantonR
CoqueTM
2006 The CTX-M beta-lactamase pandemic. Curr Opin Microbiol 9 466 475
2. PitoutJD
LauplandKB
2008 Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis 8 159 166
3. ValverdeA
CoqueTM
Sanchez-MorenoMP
RollanA
BaqueroF
2004 Dramatic increase in prevalence of fecal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae during nonoutbreak situations in Spain. J Clin Microbiol 42 4769 4775
4. PetrosinoJ
CantuCIII
PalzkillT
1998 Beta-Lactamases: protein evolution in real time. Trends Microbiol 6 323 327
5. GniadkowskiM
2008 Evolution of extended-spectrum beta-lactamases by mutation. Clin Microbiol Infect 14 Suppl 1 11 32
6. DecousserJW
PoirelL
NordmannP
2001 Characterization of a chromosomally encoded extended-spectrum class A beta-lactamase from Kluyvera cryocrescens. Antimicrob Agents Chemother 45 3595 3598
7. HumeniukC
ArletG
GautierV
GrimontP
LabiaR
2002 Beta-lactamases of Kluyvera ascorbata, probable progenitors of some plasmid-encoded CTX-M types. Antimicrob Agents Chemother 46 3045 3049
8. PoirelL
KampferP
NordmannP
2002 Chromosome-encoded Ambler class A beta-lactamase of Kluyvera georgiana, a probable progenitor of a subgroup of CTX-M extended-spectrum beta-lactamases. Antimicrob Agents Chemother 46 4038 4040
9. RodriguezMM
PowerP
RadiceM
VayC
FamigliettiA
2004 Chromosome-encoded CTX-M-3 from Kluyvera ascorbata: a possible origin of plasmid-borne CTX-M-1-derived cefotaximases. Antimicrob Agents Chemother 48 4895 4897
10. BarlowM
ReikRA
JacobsSD
MedinaM
MeyerMP
2008 High rate of mobilization for blaCTX-MS. Emerging Infectious Diseases 14 423 428
11. PoirelL
NaasT
NordmannP
2008 Genetic support of extended-spectrum beta-lactamases. Clin Microbiol Infect 14 Suppl 1 75 81
12. NovaisA
CantonR
ValverdeA
MachadoE
GalanJC
2006 Dissemination and persistence of blaCTX-M-9 are linked to class 1 integrons containing CR1 associated with defective transposon derivatives from Tn402 located in early antibiotic resistance plasmids of IncHI2, IncP1-alpha, and IncFI groups. Antimicrob Agents Chemother 50 2741 2750
13. CoqueTM
NovaisA
CarattoliA
PoirelL
PitoutJ
2008 Dissemination of clonally related Escherichia coli strains expressing extended-spectrum beta-lactamase CTX-M-15. Emerg Infect Dis 14 195 200
14. Nicolas-ChanoineMH
BlancoJ
Leflon-GuiboutV
DemartyR
AlonsoMP
2008 Intercontinental emergence of Escherichia coli clone O25:H4-ST131 producing CTX-M-15. J Antimicrob Chemother 61 273 281
15. CoqueTM
BaqueroF
CantonR
2008 Increasing prevalence of ESBL-producing Enterobacteriaceae in Europe. Euro Surveill 13 pii 19044
16. StepanovaMN
PimkinM
NikulinAA
KozyrevaVK
AgapovaED
2008 Convergent in vivo and in vitro selection of ceftazidime resistance mutations at position 167 of CTX-M-3 beta-lactamase in hypermutable Escherichia coli strains. Antimicrob Agents Chemother 52 1297 1301
17. CavacoLM
AbatihE
AarestrupFM
GuardabassiL
2008 Selection and persistence of CTX-M-producing Escherichia coli in the intestinal flora of pigs treated with amoxicillin, ceftiofur, or cefquinome. Antimicrob Agents Chemother 52 3612 3616
18. BonnetR
2004 Growing group of extended-spectrum beta-lactamases: the CTX-M enzymes. Antimicrob Agents Chemother 48 1 14
19. BauernfeindA
GrimmH
SchweighartS
1990 A new plasmidic cefotaximase in a clinical isolate of Escherichia coli. Infection 18 294 298
20. RossoliniGM
MantengoliE
2008 Antimicrobial resistance in Europe and its potential impact on empirical therapy. Clin Microbiol Infect 14 Suppl 6 2 8
21. PoirelL
GniadkowskiM
NordmannP
2002 Biochemical analysis of the ceftazidime-hydrolysing extended-spectrum beta-lactamase CTX-M-15 and of its structurally related beta-lactamase CTX-M-3. J Antimicrob Chemother 50 1031 1034
22. CartelleM
del MarTM
MolinaF
MoureR
VillanuevaR
2004 High-level resistance to ceftazidime conferred by a novel enzyme, CTX-M-32, derived from CTX-M-1 through a single Asp240-Gly substitution. Antimicrob Agents Chemother 48 2308 2313
23. NovaisA
CantonR
CoqueTM
MoyaA
BaqueroF
2008 Mutational events in ESBL-cefotaximases of the CTX-M-1 cluster involved in ceftazidime resistance. Antimicrob Agents Chemother 52 2377 82
24. BösF
PleissJ
2008 Conserved water molecules stabilize the Omega-loop in class A beta-lactamases. Antimicrob Agents Chemother 52 1072 1079
25. DelmasJ
ChenY
PratiF
RobinF
ShoichetBK
2008 Structure and dynamics of CTX-M enzymes reveal insights into substrate accommodation by extended-spectrum beta-lactamases. J Mol Biol 375 192 201
26. PoelwijkFJ
KivietDJ
WeinreichDM
TansSJ
2007 Empirical fitness landscapes reveal accessible evolutionary paths. Nature 445 383 386
27. WeinreichDM
DelaneyNF
DePristoMA
HartlDL
2006 Darwinian evolution can follow only very few mutational paths to fitter proteins. Science 312 111 114
28. OrenciaMC
YoonJS
NessJE
StemmerWP
StevensRC
2001 Predicting the emergence of antibiotic resistance by directed evolution and structural analysis. Nat Struct Biol 8 238 242
29. MartinezJL
BaqueroF
AnderssonDI
2007 Predicting antibiotic resistance. Nat Rev Micro 5 958 965
30. NovaisA
ComasI
CantonR
CoqueTM
BaqueroF
2008 Evolutionary trajectories among extended β-lactamase enzymes belonging to the CTX-M-1 cluster. 18th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Barcelona (Spain), April 2008
31. TianSF
ChenBY
ChuYZ
WangS
2008 Prevalence of rectal carriage of extended-spectrum beta-lactamase-producing Escherichia coli among elderly people in community settings in China. Can J Microbiol 54 781 785
32. NaganoY
NaganoN
WachinoJ
IshikawaK
ArakawaY
2009 Novel chimeric β-lactamase CTX-M-64, a hybrid of CTX-M-15-like and CTX-M-14 beta-lactamases, found in a Shigella sonnei strain resistant to various oxyimino-cephalosporins, including ceftazidime. Antimicrob Agents Chemother 53 69 74
33. PoirelL
NaasT
LeTI
KarimA
BingenE
2001 CTX-M-type extended-spectrum beta-lactamase that hydrolyzes ceftazidime through a single amino acid substitution in the omega loop. Antimicrob Agents Chemother 45 3355 3361
34. Maynard SmithJ
1970 Natural selection and the concept of protein space. Nature 225 563 564
35. BaqueroF
BlazquezJ
1997 Evolution of antibiotic resistance. Trends Ecol Evol 12 482 487
36. WilkinsAS
1996 Antibiotic resistance: origins, evolution and spread. Ciba Foundation Symposium, 16-18 July 1996, London. Bioessays 18 847 848
37. NegriMC
LipsitchM
BlazquezJ
LevinBR
BaqueroF
2000 Concentration-dependent selection of small phenotypic differences in TEM beta-lactamase-mediated antibiotic resistance. Antimicrob Agents Chemother 44 2485 2491
38. BlazquezJ
MorosiniMI
NegriMC
BaqueroF
2000 Selection of naturally occurring extended-spectrum TEM beta-lactamase variants by fluctuating beta-lactam pressure. Antimicrob Agents Chemother 44 2182 2184
39. WagnerA
2008 Robustness and evolvability: a paradox resolved. Proc R Soc B 275 91 100
40. LenskiRE
BarrickJE
OfriaC
2006 Balancing robustness and evolvability. PLoS Biol 4 e428 doi:10.1371/journal.pbio.0040428
41. BershteinS
GoldinK
TawfikDS
2008 Intense neutral drifts yield robust and evolvable consensus proteins. J Mol Biol 379 1029 1044
42. CharlesworthB
2009 Fundamental concepts in genetics: Effective population size and patterns of molecular evolution and variation. Nat Rev Genet 10 195 205
43. BaqueroMR
NilssonAI
del Carmen TurrientesM
SandvangD
GalanJC
2004 Polymorphic mutation frequencies in Escherichia coli: Emergence of weak mutators in clinical isolates. J Bacteriol 186 5538 5542
44. EllingtonMJ
LivermoreDM
PittTL
HallLM
WoodfordN
2006 Mutators among CTX-M beta-lactamase-producing Escherichia coli and risk for the emergence of fosfomycin resistance. J Antimicrob Chemother 58 848 852
45. BorgMA
ZarbP
FerechM
GoossensH
2008 Antibiotic consumption in southern and eastern Mediterranean hospitals: results from the ARMed project. J Antimicrob Chemother 62 830 836
46. ThompsonJD
HigginsDG
GibsonTJ
1994 CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, positions-specific gap penalties and weight matrix choice. Nucl Acids Res 22 4673 4680
47. RonquistF
HuelsenbeckJP
2003 MrBayes 3: Bayesian phylogenetic inference under mixed models. Bioinformatics 19 1572 1574
48. GuindonS
GascuelO
2003 A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Systematic Biology 52 696 704
49. PosadaD
CrandallKA
1998 Modeltest: testing the model of DNA substitution. Bioinformatics 14 917 918
50. AnisimovaM
GascuelO
2006 Approximate likelihood-ratio test for branches: a fast, accurate, and powerful alternative. Systematic Biology 55 539 522
51. SaitouN
NeiM
1987 The neighbor-joining method: A new method for reconstructing phylogenetic trees. Mol Biol Evol 4 406 425
52. KumarS
NeiM
DudleyJ
TamuraK
2008 MEGA: A biologist-centric software for evolutionary analysis of DNA and protein sequences. Brief Bioinform 9 299 306
53. BandeltHJ
ForsterP
RohlA
1999 Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol 16 37 48
54. AmblerRP
CoulsonAF
FrereJM
GhuysenJM
JorisB
1991 A standard numbering scheme for the class A beta-lactamases. Biochem J 276 (Pt 1) 269 270
55. MaddisonWP
MaddisonDR
2009 Mesquite: a modular system for evolutionary analysis, version 2.6 [computer program]
56. YangZ
2007 PAML 4: Phylogenetic Analysis by Maximum Likelihood. Mol Biol Evol 24 1586 1591
57. YangZ
NielsenR
GoldmanN
PedersenAMK
2000 Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 155 431 449
58. YangZ
WongWSW
NielsenR
2005 Bayes empirical Bayes inference of amino acid sites under positive selection. Mol Biol Evol 22 1107 1118
59. ZhangJ
NielsenR
YangZ
2005 Evaluation of an improved branch-site likelihood method for detecting positive selection at the molecular level. Mol Biol Evol 22 2472 2479
60. SprattBG
HedgePJ
te HeesenS
EdelmanA
Broome-SmithJK
1986 Kanamycin-resistant vectors that are analogues of plasmids pUC8, pUC9, pEMBL8 and pEMBL9. Gene 41 337 342
61. CondonC
WeinerJH
1988 Fumarate reductase of Escherichia coli: an investigation of function and assembly using in vivo complementation. Mol Microbiol 2 43 52
62. GillespieJH
1984 Molecular evolution over the mutational landscape. Evolution 38 1116 1129
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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