EPIDEMIC DIARRHEA AMONG INFANTS ASSOCIATED WITH THE ISOLATION OF A NEW SEROTYPE OF ESCHERICHIA COLI: E. COLI 0127:B8

PEDIATRICS ◽  
1955 ◽  
Vol 16 (2) ◽  
pp. 215-227
Author(s):  
Merlin L. Cooper ◽  
Edward W. Walters ◽  
Helen M. Keller ◽  
James M. Sutherland ◽  
Hollis J. Wiseman
Keyword(s):  
Escherichia Coli ◽  
Rectal Swab ◽  
Specific Treatment ◽  
First Year ◽  
Average Dose ◽  
Clinical Value ◽  
E Coli ◽  
Severe Diarrhea ◽  
First Year Of Life

During an outbreak of epidemic diarrhea a new serotype of Escherichia coli: E. coli 0127:B8, was isolated from 44 of 145 infants and from 1 nurse among 82 adult personnel in attendance. Among the 44 infants whose rectal swab cultures were positive, 20 were in the first month of life, 16 were 2 to 6 months of age, and 6 were 7 to 12 months of age, a total of 42 being in the first year of life. Severe epidemic diarrhea associated with the presence of E. coli 0127:B8 was characterized by the sudden development of extreme abdominal distention among some of the infants; explosive onset of diarrhea and the presence of a pungent, musty, objectionable odor not noticed around other patients with diarrhea. E. coli 0127: B8 was isolated more frequently while the patients were having diarrhea. Neomycin® was used orally for the specific treatment of patients with diarrhea. The early dosage was small due to our caution in using a new antibiotic. Over the 4 months period of this study the dosage was gradually increased. The average dose was 40 mg./kg./day for the patients with positive cultures and 46 mg./kg./day for those with negative cultures. Of 22 patients with positive cultures, 12 who were treated with Neomycin® alone or in addition to other antibiotics continued to show the presence of E. coli 0127:B8 after Neomycin® therapy had been terminated; however, only 2 of these patients had recurrence of diarrhea, both having had negative cultures while receiving Neomycin®. The administration of Neomycin® to every infant on the 2 wards, regardless of clinical condition, was followed by a decreasing incidence of diarrhea and decreasing detection of E. coli 0127:B8. The dose of Neomycin® was 40 to 50 mg./kg./day. It is our feeling that Neomycin® administered orally was of definite clinical value therapeutically and prophylactically but in the dosage used was inadequate bacteriologically. Four deaths occurred among the 44 infants whose rectal swab cultures were positive for E. coli 0127:B8 and necropsy studies were made on each. A hemorrhagic enteritis was present in 3 infants and in the fourth infant the cause of death was a congenital heart condition. Death of 1 patient with negative rectal swab cultures may very likely be attributed to severe diarrhea. Sera from patients and personnel failed to show the presence of agglutinins for E. coli 0127:B8. in vitro sensitivity tests showed that the order of decreasing bactericidal effectiveness of 5 antibiotics for E. coli 027:B8 was polymyxin, Neomycin®, chloramphenicol, Achromycin®, and Terramycin®. All strains were resistant to dihydrostreptomycin and sodium sulfadiazine. Only the last strains isolated from 2 patients showed increased resistance to Neomycin®, four-and sixteenfold when compared with the first strains isolated from the same patients.

COMPARATIVE FREQUENCY OF DETECTION OF ENTEROPATHOGENIC E. COLI, SALMONELLA AND SHIGELLA IN RECTAL SWAB CULTURES FROM INFANTS AND YOUNG CHILDREN

PEDIATRICS ◽  
1957 ◽  
Vol 19 (3) ◽  
pp. 411-423
Author(s):  
Merlin L. Cooper ◽  
Helen M. Keller ◽  
Edward W. Walters
Keyword(s):  
Young Children ◽  
Rectal Swab ◽  
Multiple Infections ◽  
First Year ◽  
Isolation And Identification ◽  
E Coli ◽  
Salmonella Infections ◽  
Number Of Patients ◽  
First Year Of Life ◽  
Infants And Young Children

The present report supplies the details and results of a study of 2,865 patients during a period of 2 years, March 1, 1954, to March 1, 1956. The purpose of the study was to determine the comparative frequency of isolation of Salmonella, Shigella and nine serotypes of enteropathogenic E. coli from rectal swab cultures obtained from infants and young children admitted to the Children's Hospital. The technic for the isolation and identification of enteropathogenic E. coli is described. A diagnostic polyvalent E. coli antiserum prepared in our laboratory was very helpful in the preliminary detection of nine serotypes of enteropathogenic E. coli. Salmonellae were isolated from 85 patients, Shigellae from 88 and one of the nine serotypes of enteropathogenic E. coli from each of 188 patients. Seventeen serotypes of Salmonella were isolated from 85 patients. Salmonella sp. (Type oranienburg) and Sal. typhimurium were isolated most frequently. Shigellae were isolated from a total of 88 patients; Sh. sonnei from 53 and five serotypes of Sh. flexneri from 35 patients. One of the nine serotypes of enteropathogenic E. coli was isolated from each of 188 patients. E. coli 055:B5 was detected in cultures from 63 patients and was detected most frequently. E. coli 0111:B4, 0126:B16 and 026:B6 were found next most frequently. Of the 361 patients from whom Salmonella, Shigella or enteropathogenic E. coli were isolated, rectal swab cultures were obtained at the time of admission from 317. Of these, 287 (91%) were positive. The incidence of diarrhea in the three groups was comparable: 95% of the patients from whom Salmonellae were isolated, 98% of patients from whom Shigellae were isolated and 92% of patients harboring enteropathogenic E. coli. Infections due to Salmonella or enteropathogenic E. coli were more frequent in the first year of life and infections due to Shigella occurred more frequently in the second year of life. The majority of patients with diarrhea and with rectal swab cultures negative for Salmonella, Shigella and enteropathogenic E. coli were in the first year of life. The incidence of Salmonella infections did not show any seasonal predominance; the Shigella infections were most frequent in September and October and the enteropathogenic E. coli infections in November and October. The highest incidence of diarrheal infections among patients whose rectal swab cultures were negative for these three groups of bacteria occurred in December and January of each of the 2 years of this study. The incidence of enteropathogenic E. coli infections exceeded those due to Shigella or Salmonella during 15 of the 24 months of this study. Sporadic infections due to these three groups of bacteria occurred throughout the 2-year period. Successive and/or multiple infections with Salmonella, Shigella or enteropathogenic E. coli occurred in 15 paients. Infection with one serotype of enteropathogenic E. coli did not protect seven patients from subsequent infection with another serotype. The convalescent carrier rate was 36.6% for the patients with Salmonella infections, 2.6% for those with Shigella infections and 8.3% for those from whom enteropathogenic E. coli had been isolated. The mortality rate was 1.2% among patients with Salmonella infections and 1.6% among the patients from whom enteropathogenic E. coli had been isolated. None of the patients with Shigella infections died. The large number of patients, 889, with diarrhea and with rectal swab cultures negative for Salmonella, Shigella and enteropathogenic E. coli indicates a need for continued investigation into the etiology of diarrhea in infants and young children.

scholarly journals Synthesis, in silico studies and antibacterial assessment of α-amino phosphonates derivatives

Bionatura ◽  
2021 ◽  
Vol 3 (3) ◽  
pp. 1986-1991
Author(s):  
Bouchra El Khalfi ◽  
Boutaina Addoum ◽  
Suhayla Harrati ◽  
Abdelhakim Elmakssoudi ◽  
Abdelaziz Soukri
Keyword(s):  
Escherichia Coli ◽  
Antibacterial Agents ◽  
Specific Treatment ◽  
Comprehensive Understanding ◽  
E Coli ◽  
Antibacterial Screening ◽  
In Silico Studies ◽  
Resistant Strains ◽  
Amino Phosphonates

The widespread of multi-resistant strains due to the lack of specific treatment and the propagation of infectious diseases requires all resources to remedy this scourge. This study is therefore aimed to assess the antibacterial activity of four synthetic α-Aminophosphonate 4(a-d). Methods: Firstly, α-Aminophosphonate has been synthesized and characterized, then molecular docking of these compounds 4(a-d) into the active binding site of Escherichia coli MurB enzyme (PDB Id: 1MBT) was performed to gain a comprehensive understanding of their biological activity. These compounds have been subjected to in vitro antibacterial screening against three multi-resistant strains E. coli, S. aureus, and L. monocytogenes. These compounds showed crucial antibacterial behavior against all studied strains. Thus, their docking estimation supported the in vitro results and showed that the 4c derivative has considerable binding energy towards the active site of Escherichia coli MurB. These findings provide critical information for the exploration of α-amino phosphonates as novel antibacterial agents.

Substituted 4-Formyl-2H-chromen-2-ones: Their Reaction with N-(2,3,4,6-Tetra-Oacetyl- β-D-galactopyranosyl)thiosemicarbazide, Antibacterial and Antifungal Activity of Their Thiosemicarbazone Products

2020 ◽  
Vol 24 (19) ◽  
pp. 2272-2282
Author(s):  
Vu Ngoc Toan ◽  
Nguyen Minh Tri ◽  
Nguyen Dinh Thanh
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Candida Albicans ◽  
Selenium Dioxide ◽  
Antibacterial And Antifungal Activity ◽  
E Coli ◽  
Antibacterial And Antifungal Activities ◽  
Alkyl Ethers ◽  
Antibacterial And Antifungal

Several 6- and 7-alkoxy-2-oxo-2H-chromene-4-carbaldehydes were prepared from corresponding alkyl ethers of 6- and 7-hydroxy-4-methyl-2-oxo-2H-chromen-2-ones by oxidation using selenium dioxide. 6- and 7-Alkoxy-4-methyl-2H-chromenes were obtained with yields of 57-85%. Corresponding 4-carbaldehyde derivatives were prepared with yields of 41-67%. Thiosemicarbazones of these aldehydes with D-galactose moiety were synthesized by reaction of these aldehydes with N-(2,3,4,6-tetra-O-acetyl-β-Dgalactopyranosyl) thiosemicarbazide with yields of 62-74%. These thiosemicarbazones were screened for their antibacterial and antifungal activities in vitro against bacteria, such as Staphylococcus aureus, Escherichia coli, and fungi, such as Aspergillus niger, Candida albicans. Several compounds exhibited strong inhibitory activity with MIC values of 0.78- 1.56 μM, including 8a (against S. aureus, E. coli, and C. albicans), 8d (against E. coli and A. niger), 9a (against S. aureus), and 9c (against S. aureus and C. albicans).

scholarly journals In vitro activity of antimicrobial peptide CDP-B11 alone and in combination with colistin against colistin-resistant and multidrug-resistant Escherichia coli

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kaitlin S. Witherell ◽  
Jason Price ◽  
Ashok D. Bandaranayake ◽  
James Olson ◽  
Douglas R. Call
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Peptide ◽  
Membrane Integrity ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Multidrug Resistant Bacteria ◽  
E Coli ◽  
Minimal Media

AbstractMultidrug-resistant bacteria are a growing global concern, and with increasingly prevalent resistance to last line antibiotics such as colistin, it is imperative that alternative treatment options are identified. Herein we investigated the mechanism of action of a novel antimicrobial peptide (CDP-B11) and its effectiveness against multidrug-resistant bacteria including Escherichia coli #0346, which harbors multiple antibiotic-resistance genes, including mobilized colistin resistance gene (mcr-1). Bacterial membrane potential and membrane integrity assays, measured by flow cytometry, were used to test membrane disruption. Bacterial growth inhibition assays and time to kill assays measured the effectiveness of CDP-B11 alone and in combination with colistin against E. coli #0346 and other bacteria. Hemolysis assays were used to quantify the hemolytic effects of CDP-B11 alone and in combination with colistin. Findings show CDP-B11 disrupts the outer membrane of E. coli #0346. CDP-B11 with colistin inhibits the growth of E. coli #0346 at ≥ 10× lower colistin concentrations compared to colistin alone in Mueller–Hinton media and M9 media. Growth is significantly inhibited in other clinically relevant strains, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. In rich media and minimal media, the drug combination kills bacteria at a lower colistin concentration (1.25 μg/mL) compared to colistin alone (2.5 μg/mL). In minimal media, the combination is bactericidal with killing accelerated by up to 2 h compared to colistin alone. Importantly, no significant red blood hemolysis is evident for CDP-B11 alone or in combination with colistin. The characteristics of CDP-B11 presented here indicate that it can be used as a potential monotherapy or as combination therapy with colistin for the treatment of multidrug-resistant infections, including colistin-resistant infections.

scholarly journals Lysyl-tRNA synthetase from Escherichia coli K12. Chromatographic heterogeneity and the lysU-gene product

1987 ◽  
Vol 248 (1) ◽  
pp. 43-51 ◽  
Author(s):  
J Charlier ◽  
R Sanchez
Keyword(s):  
Escherichia Coli ◽  
Gene Product ◽  
Activity Ratio ◽  
Deae Cellulose ◽  
Trna Synthetase ◽  
Trna Synthetases ◽  
E Coli ◽  
Aminoacyl Trna Synthetases

In contrast with most aminoacyl-tRNA synthetases, the lysyl-tRNA synthetase of Escherichia coli is coded for by two genes, the normal lysS gene and the inducible lysU gene. During its purification from E. coli K12, lysyl-tRNA synthetase was monitored by its aminoacylation and adenosine(5′)tetraphospho(5′)adenosine (Ap4A) synthesis activities. Ap4A synthesis was measured by a new assay using DEAE-cellulose filters. The heterogeneity of lysyl-tRNA synthetase (LysRS) was revealed on hydroxyapatite; we focused on the first peak, LysRS1, because of its higher Ap4A/lysyl-tRNA activity ratio at that stage. Additional differences between LysRS1 and LysRS2 (major peak on hydroxyapatite) were collected. LysRS1 was eluted from phosphocellulose in the presence of the substrates, whereas LysRS2 was not. Phosphocellulose chromatography was used to show the increase of LysRS1 in cells submitted to heat shock. Also, the Mg2+ optimum in the Ap4A-synthesis reaction is much higher for LysRS1. LysRS1 showed a higher thermostability, which was specifically enhanced by Zn2+. These results in vivo and in vitro strongly suggest that LysRS1 is the heat-inducible lysU-gene product.

scholarly journals A Rhodobacter sphaeroides Protein Mechanistically Similar to Escherichia coli DksA Regulates Photosynthetic Growth

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Christopher W. Lennon ◽  
Kimberly C. Lemmer ◽  
Jessica L. Irons ◽  
Max I. Sellman ◽  
Timothy J. Donohue ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Structure Function ◽  
Rhodobacter Sphaeroides ◽  
Fatty Acid Content ◽  
Regulatory Protein ◽  
Growth Conditions ◽  
Globular Domain ◽  
Content Type ◽  
E Coli

ABSTRACTDksA is a global regulatory protein that, together with the alarmone ppGpp, is required for the “stringent response” to nutrient starvation in the gammaproteobacteriumEscherichia coliand for more moderate shifts between growth conditions. DksA modulates the expression of hundreds of genes, directly or indirectly. Mutants lacking a DksA homolog exhibit pleiotropic phenotypes in other gammaproteobacteria as well. Here we analyzed the DksA homolog RSP2654 in the more distantly relatedRhodobacter sphaeroides, an alphaproteobacterium. RSP2654 is 42% identical and similar in length toE. coliDksA but lacks the Zn finger motif of theE. coliDksA globular domain. Deletion of the RSP2654 gene results in defects in photosynthetic growth, impaired utilization of amino acids, and an increase in fatty acid content. RSP2654 complements the growth and regulatory defects of anE. colistrain lacking thedksAgene and modulates transcriptionin vitrowithE. coliRNA polymerase (RNAP) similarly toE. coliDksA. RSP2654 reduces RNAP-promoter complex stabilityin vitrowith RNAPs fromE. coliorR. sphaeroides, alone and synergistically with ppGpp, suggesting that even though it has limited sequence identity toE. coliDksA (DksAEc), it functions in a mechanistically similar manner. We therefore designate the RSP2654 protein DksARsp. Our work suggests that DksARsphas distinct and important physiological roles in alphaproteobacteria and will be useful for understanding structure-function relationships in DksA and the mechanism of synergy between DksA and ppGpp.IMPORTANCEThe role of DksA has been analyzed primarily in the gammaproteobacteria, in which it is best understood for its role in control of the synthesis of the translation apparatus and amino acid biosynthesis. Our work suggests that DksA plays distinct and important physiological roles in alphaproteobacteria, including the control of photosynthesis inRhodobacter sphaeroides. The study of DksARsp, should be useful for understanding structure-function relationships in the protein, including those that play a role in the little-understood synergy between DksA and ppGpp.

scholarly journals Enhancement of the Efficiency of Secretion of Heterologous Lipase in Escherichia coli by Directed Evolution of the ABC Transporter System

2005 ◽  
Vol 71 (7) ◽  
pp. 3468-3474 ◽  
Author(s):  
Gyeong Tae Eom ◽  
Jae Kwang Song ◽  
Jung Hoon Ahn ◽  
Yeon Soo Seo ◽  
Joon Shick Rhee
Keyword(s):  
Escherichia Coli ◽  
Directed Evolution ◽  
Abc Transporter ◽  
Microtiter Plate ◽  
Single Amino Acid ◽  
Wild Type ◽  
E Coli ◽  
Single Amino Acid Change ◽  
Secretion Efficiency

ABSTRACT The ABC transporter (TliDEF) from Pseudomonas fluorescens SIK W1, which mediated the secretion of a thermostable lipase (TliA) into the extracellular space in Escherichia coli, was engineered using directed evolution (error-prone PCR) to improve its secretion efficiency. TliD mutants with increased secretion efficiency were identified by coexpressing the mutated tliD library with the wild-type tliA lipase in E. coli and by screening the library with a tributyrin-emulsified indicator plate assay and a microtiter plate-based assay. Four selected mutants from one round of error-prone PCR mutagenesis, T6, T8, T24, and T35, showed 3.2-, 2.6-, 2.9-, and 3.0-fold increases in the level of secretion of TliA lipase, respectively, but had almost the same level of expression of TliD in the membrane as the strain with the wild-type TliDEF transporter. These results indicated that the improved secretion of TliA lipase was mediated by the transporter mutations. Each mutant had a single amino acid change in the predicted cytoplasmic regions in the membrane domain of TliD, implying that the corresponding region of TliD was important for the improved and successful secretion of the target protein. We therefore concluded that the efficiency of secretion of a heterologous protein in E. coli can be enhanced by in vitro engineering of the ABC transporter.

scholarly journals In vitro reconstitution of the GTPase-associated centre of the archaebacterial ribosome: the functional features observed in a hybrid form with Escherichia coli 50S subunits

2006 ◽  
Vol 396 (3) ◽  
pp. 565-571 ◽  
Author(s):  
Takaomi Nomura ◽  
Kohji Nakano ◽  
Yasushi Maki ◽  
Takao Naganuma ◽  
Takashi Nakashima ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Ribosomal Proteins ◽  
Synthetic Activity ◽  
23S Rrna ◽  
Elongation Factors ◽  
Hybrid Form ◽  
Pyrococcus Horikoshii ◽  
E Coli ◽  
Functional Features

We cloned the genes encoding the ribosomal proteins Ph (Pyrococcus horikoshii)-P0, Ph-L12 and Ph-L11, which constitute the GTPase-associated centre of the archaebacterium Pyrococcus horikoshii. These proteins are homologues of the eukaryotic P0, P1/P2 and eL12 proteins, and correspond to Escherichia coli L10, L7/L12 and L11 proteins respectively. The proteins and the truncation mutants of Ph-P0 were overexpressed in E. coli cells and used for in vitro assembly on to the conserved domain around position 1070 of 23S rRNA (E. coli numbering). Ph-L12 tightly associated as a homodimer and bound to the C-terminal half of Ph-P0. The Ph-P0·Ph-L12 complex and Ph-L11 bound to the 1070 rRNA fragments from the three biological kingdoms in the same manner as the equivalent proteins of eukaryotic and eubacterial ribosomes. The Ph-P0·Ph-L12 complex and Ph-L11 could replace L10·L7/L12 and L11 respectively, on the E. coli 50S subunit in vitro. The resultant hybrid ribosome was accessible for eukaryotic, as well as archaebacterial elongation factors, but not for prokaryotic elongation factors. The GTPase and polyphenylalanine-synthetic activity that is dependent on eukaryotic elongation factors was comparable with that of the hybrid ribosomes carrying the eukaryotic ribosomal proteins. The results suggest that the archaebacterial proteins, including the Ph-L12 homodimer, are functionally accessible to eukaryotic translation factors.

scholarly journals Promiscuous Cross-seeding between Bacterial Amyloids Promotes Interspecies Biofilms

2012 ◽  
Vol 287 (42) ◽  
pp. 35092-35103 ◽  
Author(s):  
Yizhou Zhou ◽  
Daniel Smith ◽  
Bryan J. Leong ◽  
Kristoffer Brännström ◽  
Fredrik Almqvist ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Shewanella Oneidensis ◽  
Bacterial Attachment ◽  
Surface Attachment ◽  
E Coli ◽  
Amyloid Aggregates ◽  
Functional Amyloids ◽  
Biofilm Development ◽  
Distant Homolog

Amyloids are highly aggregated proteinaceous fibers historically associated with neurodegenerative conditions including Alzheimers, Parkinsons, and prion-based encephalopathies. Polymerization of amyloidogenic proteins into ordered fibers can be accelerated by preformed amyloid aggregates derived from the same protein in a process called seeding. Seeding of disease-associated amyloids and prions is highly specific and cross-seeding is usually limited or prevented. Here we describe the first study on the cross-seeding potential of bacterial functional amyloids. Curli are produced on the surface of many Gram-negative bacteria where they facilitate surface attachment and biofilm development. Curli fibers are composed of the major subunit CsgA and the nucleator CsgB, which templates CsgA into fibers. Our results showed that curli subunit homologs from Escherichia coli, Salmonella typhimurium LT2, and Citrobacter koseri were able to cross-seed in vitro. The polymerization of Escherichia coli CsgA was also accelerated by fibers derived from a distant homolog in Shewanella oneidensis that shares less than 30% identity in primary sequence. Cross-seeding of curli proteins was also observed in mixed colony biofilms with E. coli and S. typhimurium. CsgA was secreted from E. coli csgB− mutants assembled into fibers on adjacent S. typhimurium that presented CsgB on its surfaces. Similarly, CsgA was secreted by S. typhimurium csgB− mutants formed curli on CsgB-presenting E. coli. This interspecies curli assembly enhanced bacterial attachment to agar surfaces and supported pellicle biofilm formation. Collectively, this work suggests that the seeding specificity among curli homologs is relaxed and that heterogeneous curli fibers can facilitate multispecies biofilm development.

scholarly journals Biological Cost of Single and Multiple Norfloxacin Resistance Mutations in Escherichia coli Implicated in Urinary Tract Infections

2005 ◽  
Vol 49 (6) ◽  
pp. 2343-2351 ◽  
Author(s):  
Patricia Komp Lindgren ◽  
Linda L. Marcusson ◽  
Dorthe Sandvang ◽  
Niels Frimodt-Møller ◽  
Diarmaid Hughes
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract ◽  
Infection Model ◽  
Resistance Mutations ◽  
Topoisomerase Iv ◽  
E Coli ◽  
Tract Infections ◽  
Subsequent Selection

ABSTRACT Resistance to fluoroquinolones in urinary tract infection (UTIs) caused by Escherichia coli is associated with multiple mutations, typically those that alter DNA gyrase and DNA topoisomerase IV and those that regulate AcrAB-TolC-mediated efflux. We asked whether a fitness cost is associated with the accumulation of these multiple mutations. Mutants of the susceptible E. coli UTI isolate Nu14 were selected through three to five successive steps with norfloxacin. Each selection was performed with the MIC of the selected strain. After each selection the MIC was measured; and the regions of gyrA, gyrB, parC, and parE, previously associated with resistance mutations, and all of marOR and acrR were sequenced. The first selection step yielded mutations in gyrA, gyrB, and marOR. Subsequent selection steps yielded mutations in gyrA, parE, and marOR but not in gyrB, parC, or acrR. Resistance-associated mutations were identified in almost all isolates after selection steps 1 and 2 but in less than 50% of isolates after subsequent selection steps. Selected strains were competed in vitro, in urine, and in a mouse UTI infection model against the starting strain, Nu14. First-step mutations were not associated with significant fitness costs. However, the accumulation of three or more resistance-associated mutations was usually associated with a large reduction in biological fitness, both in vitro and in vivo. Interestingly, in some lineages a partial restoration of fitness was associated with the accumulation of additional mutations in late selection steps. We suggest that the relative biological costs of multiple mutations may influence the evolution of E. coli strains that develop resistance to fluoroquinolones.

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