scholarly journals Understanding the basis of antibiotic resistance: a platform for drug discovery

Microbiology ◽  
2014 ◽  
Vol 160 (11) ◽  
pp. 2366-2373 ◽  
Author(s):  
Laura J. V. Piddock
Keyword(s):  
Antibiotic Resistance ◽  
Salmonella Enterica ◽  
Efflux Pump ◽  
Antibiotic Resistance Genes ◽  
Multi Drug Resistance ◽  
Annual Conference ◽  
Altered Expression ◽  
Genetic Inactivation ◽  
Fluoroquinolone Antibiotics ◽  
Serovar Typhimurium

There are numerous genes in Salmonella enterica serovar Typhimurium that can confer resistance to fluoroquinolone antibiotics, including those that encode topoisomerase proteins, the primary targets of this class of drugs. However, resistance is often multifactorial in clinical isolates and it is not uncommon to also detect mutations in genes that affect the expression of proteins involved in permeability and multi-drug efflux. The latter mechanism, mediated by tripartite efflux systems, such as that formed by the AcrAB–TolC system, confers inherent resistance to many antibiotics, detergents and biocides. Genetic inactivation of efflux genes gives multi-drug hyper-susceptibility, and in the absence of an intact AcrAB–TolC system some chromosomal and transmissible antibiotic resistance genes no longer confer clinically relevant levels of resistance. Furthermore, a functional multi-drug resistance efflux pump, such as AcrAB–TolC, is required for virulence and the ability to form a biofilm. In part, this is due to altered expression of virulence and biofilm genes being sensitive to efflux status. Efflux pump expression can be increased, usually due to mutations in regulatory genes, and this confers resistance to clinically useful drugs such as fluoroquinolones and β-lactams. Here, I discuss some of the work my team has carried out characterizing the mechanisms of antibiotic resistance in Salmonella enterica serovar Typhimurium from the late 1980s to 2014. A video of this Prize Lecture, presented at the Society for General Microbiology Annual Conference 2014, can be viewed via this link: https://www.youtube.com/watch?v=MCRumMV99Yw.

scholarly journals Antibiotic Resistance Genes and Salmonella Genomic Island 1 in Salmonella enterica Serovar Typhimurium Isolated in Italy

2002 ◽  
Vol 46 (9) ◽  
pp. 2821-2828 ◽  
Author(s):  
Alessandra Carattoli ◽  
Emma Filetici ◽  
Laura Villa ◽  
Anna Maria Dionisi ◽  
Antonia Ricci ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Salmonella Enterica ◽  
Genomic Island ◽  
Antibiotic Resistance Genes ◽  
Tetracycline Resistance ◽  
Gene Cassette ◽  
Multidrug Resistant ◽  
Phage Types ◽  
Serovar Typhimurium

ABSTRACT Fifty-four epidemiologically unrelated multidrug-resistant Salmonella enterica serovar Typhimurium isolates, collected between 1992 and 2000 in Italy, were analyzed for the presence of integrons. Strains were also tested for Salmonella genomic island 1 (SGI1), carrying antibiotic resistance genes in DT104 strains. A complete SGI1 was found in the majority of the DT104 strains. Two DT104 strains, showing resistance to streptomycin-spectinomycin and sulfonamides, carried a partially deleted SGI1 lacking the flost , tetR, and tetA genes, conferring chloramphenicol-florfenicol and tetracycline resistance, and the integron harboring the pse-1 gene cassette, conferring ampicillin resistance. The presence of SGI1 was also observed in serovar Typhimurium strains belonging to other phage types, suggesting either the potential mobility of this genomic island or changes in the phage-related phenotype of DT104 strains.

scholarly journals Gene Transfer between Salmonella enterica Serovar Typhimurium inside Epithelial Cells

2002 ◽  
Vol 184 (8) ◽  
pp. 2235-2242 ◽  
Author(s):  
Gayle C. Ferguson ◽  
Jack A. Heinemann ◽  
Martin A. Kennedy
Keyword(s):  
Antibiotic Resistance ◽  
Gene Transfer ◽  
Salmonella Enterica ◽  
Genetically Modified Organisms ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Antibiotic Resistance Genes ◽  
Human Cells ◽  
Serovar Typhimurium ◽  
Cultured Human Cells ◽  
Eukaryotic Organisms

ABSTRACT Virulence and antibiotic resistance genes transfer between bacteria by bacterial conjugation. Conjugation also mediates gene transfer from bacteria to eukaryotic organisms, including yeast and human cells. Predicting when and where genes transfer by conjugation could enhance our understanding of the risks involved in the release of genetically modified organisms, including those being developed for use as vaccines. We report here that Salmonella enterica serovar Typhimurium conjugated inside cultured human cells. The DNA transfer from donor to recipient bacteria was proportional to the probability that the two types of bacteria occupied the same cell, which was dependent on viable and invasive bacteria and on plasmid tra genes. Based on the high frequencies of gene transfer between bacteria inside human cells, we suggest that such gene transfers occur in situ. The implications of gene transfer between bacteria inside human cells, particularly in the context of antibiotic resistance, are discussed.

scholarly journals Multidrug-Resistant Salmonella enterica Serovar Paratyphi A Harbors IncHI1 Plasmids Similar to Those Found in Serovar Typhi

2007 ◽  
Vol 189 (11) ◽  
pp. 4257-4264 ◽  
Author(s):  
Kathryn E. Holt ◽  
Nicholas R. Thomson ◽  
John Wain ◽  
Minh Duy Phan ◽  
Satheesh Nair ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Salmonella Enterica ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Mobile Elements ◽  
Mobile Dna ◽  
Serovar Typhimurium ◽  
Dna Elements ◽  
Dna Backbone

ABSTRACT Salmonella enterica serovars Typhi and Paratyphi A cause systemic infections in humans which are referred to as enteric fever. Multidrug-resistant (MDR) serovar Typhi isolates emerged in the 1980s, and in recent years MDR serovar Paratyphi A infections have become established as a significant problem across Asia. MDR in serovar Typhi is almost invariably associated with IncHI1 plasmids, but the genetic basis of MDR in serovar Paratyphi A has remained predominantly undefined. The DNA sequence of an IncHI1 plasmid, pAKU_1, encoding MDR in a serovar Paratyphi A strain has been determined. Significantly, this plasmid shares a common IncHI1-associated DNA backbone with the serovar Typhi plasmid pHCM1 and an S. enterica serovar Typhimurium plasmid pR27. Plasmids pAKU_1 and pHCM1 share 14 antibiotic resistance genes encoded within similar mobile elements, which appear to form a 24-kb composite transposon that has transferred as a single unit into different positions into their IncHI1 backbones. Thus, these plasmids have acquired similar antibiotic resistance genes independently via the horizontal transfer of mobile DNA elements. Furthermore, two IncHI1 plasmids from a Vietnamese isolate of serovar Typhi were found to contain features of the backbone sequence of pAKU_1 rather than pHCM1, with the composite transposon inserted in the same location as in the pAKU_1 sequence. Our data show that these serovar Typhi and Paratyphi A IncHI1 plasmids share highly conserved core DNA and have acquired similar mobile elements encoding antibiotic resistance genes in past decades.

scholarly journals Diverse and Flexible Transmission of fosA3 Associated with Heterogeneous Multidrug Resistance Regions in Salmonella enterica Serovar Typhimurium and Indiana Isolates

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Liang-Xing Fang ◽  
Qi Jiang ◽  
Guo-Hui Deng ◽  
Bing He ◽  
Ruan-Yang Sun ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Multidrug Resistance ◽  
Resistance Genes ◽  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Antibiotic Resistance Genes ◽  
Guangdong Province ◽  
Great Flexibility ◽  
Serovar Typhimurium ◽  
M 14

ABSTRACT We identified fosA3 at a rate of 2.6% in 310 Salmonella isolates from food animals in Guangdong province, China. The fosA3 gene was genetically linked to diverse antibiotic resistance genes (ARGs), including mcr-1, blaCTX-M-14/55, oqxAB, and rmtB. These gene combinations were embedded in heterogeneous fosA3-containing multidrug resistance regions on the transferable ST3-IncHI2 and F33:A−:B− plasmids and the chromosome. This indicated a great flexibility of fosA3 cotransmission with multiple important ARGs among Salmonella species.

scholarly journals Evidence for an Efflux Pump Mediating Multiple Antibiotic Resistance in Salmonella enterica Serovar Typhimurium

2000 ◽  
Vol 44 (11) ◽  
pp. 3118-3121 ◽  
Author(s):  
Laura J. V. Piddock ◽  
David G. White ◽  
Karl Gensberg ◽  
Lilian Pumbwe ◽  
Deborah J. Griggs
Keyword(s):  
Antibiotic Resistance ◽  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Efflux Pump ◽  
Northern Blotting ◽  
Multiple Antibiotic Resistance ◽  
Reverse Transcription Pcr ◽  
Carbonyl Cyanide ◽  
Serovar Typhimurium

ABSTRACT The mechanism of multiple antibiotic resistance in six isolates ofSalmonella enterica serovar Typhimurium recovered from a patient treated with ciprofloxacin was studied to investigate the role of efflux in the resistance phenotype. Compared to the patient's pretherapy isolate (L3), five of six isolates accumulated less ciprofloxacin, three of six isolates accumulated less chloramphenicol, and all six accumulated less tetracycline. The accumulation of one or more antibiotics was increased by carbonyl cyanidem-chlorophenylhydrazone to concentrations similar to those accumulated by L3 for all isolates except one, in which accumulation of all three agents remained approximately half that of L3. All isolates had the published wild-type sequences of marO andmarR. No increased expression of marA,tolC, or soxS was observed by Northern blotting; however, three isolates showed increased expression ofacrB, which was confirmed by quantitative competitive reverse transcription-PCR. However, there were no mutations withinacrR or the promoter region of acrAB in any of the isolates.

scholarly journals Distribution of prophages and SGI-1 antibiotic-resistance genes among different Salmonella enterica serovar Typhimurium isolates

Microbiology ◽  
2006 ◽  
Vol 152 (7) ◽  
pp. 2137-2147 ◽  
Author(s):  
Armand P. H. M. Hermans ◽  
Annelien M. Beuling ◽  
Angela H. A. M. van Hoek ◽  
Henk J. M. Aarts ◽  
Tjakko Abee ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Salmonella Enterica ◽  
Phage Type ◽  
Antibiotic Resistance Genes ◽  
Subtractive Hybridization ◽  
The Novel ◽  
Additional Information ◽  
Phage Types ◽  
Serovar Typhimurium

Recently, the authors identified Salmonella enterica serovar Typhimurium (S. Typhimurium) definitive type (DT)104-specific sequences of mainly prophage origin by genomic subtractive hybridization. In the present study, the distribution of the prophages identified, ST104 and ST64B, and the novel prophage remnant designated prophage ST104B, was tested among 23 non-DT104 S. Typhimurium isolates of different phage types and 19 isolates of the DT104 subtypes DT104A, DT104B low and DT104L, and the DT104-related type U302. The four S. Typhimurium prophages Gifsy-1, Gifsy-2, Fels-1 and Fels-2 were also included. Analysis of prophage distribution in different S. Typhimurium isolates may supply additional information to enable development of a molecular method as an alternative to phage typing. Furthermore, the presence of the common DT104 antibiotic resistance genes for the penta-resistance type ACSSuT, aadA2, floR, pse-1, sul1 and tet(G), was also studied because of the authors' focus on this emerging type. Based on differences in prophage presence within their genome, it was possible to divide S. Typhimurium isolates into 12 groups. Although no clear relationship was found between different phage type and prophage presence, discrimination could be made between the different DT104 subtypes based on diversity in the presence of prophages ST104, ST104B and ST64B. The novel prophage remnant ST104B, which harbours a homologue of the Escherichia coli O157 : H7 HldD LPS assembly-related protein, was identified only in the 14 DT104L isolates and in the DT104-related U302 isolate. In conclusion, the presence of the genes for penta-resistance type ACSSuT, the HldD homologue containing ST104 prophage remnant and phage type DT104L are most likely common features of the emerging subtype of S. Typhimurium DT104.

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