scholarly journals Evolution and Dissemination of OqxAB-Like Efflux Pumps, an Emerging Quinolone Resistance Determinant among Members of Enterobacteriaceae

2015 ◽  
Vol 59 (6) ◽  
pp. 3290-3297 ◽  
Author(s):  
Marcus Ho Yin Wong ◽  
Edward Wai Chi Chan ◽  
Sheng Chen
Keyword(s):  
Efflux Pump ◽  
Phylogenetic Analyses ◽  
Bacterial Species ◽  
Fold Increase ◽  
Quinolone Resistance ◽  
Cross Resistance ◽  
Phenotypic Characteristics ◽  
Gram Negative ◽  
Content Type ◽  
Elevated Expression

ABSTRACTThe OqxAB efflux pump, a plasmid-mediated quinolone resistance (PMQR) determinant, has become increasingly prevalent among members ofEnterobacteriaceaeover the past decade. To investigate the evolution and dissemination routes of theoqxABoperon, we assessed the prevalence ofoqxAB-like elements among various Gram-negative bacterial species and analyzed the genotypic and phenotypic characteristics of organisms harboring such elements. With a comprehensive genotyping approach, a chromosome-basedoqxABoperon was detectable in allKlebsiella pneumoniaestrains tested, including organisms isolated before the year 1984. Sequence and phylogenetic analyses confirmed that theoqxABoperon inK. pneumoniaeisolates was genetically closest to their plasmid-borne counterparts recoverable only fromEscherichia coliandSalmonellaisolates collected from the year 2003 onward. Chromosomal elements with much lower sequence homology were also found among theEnterobacterspp. but not other Gram-negative species. Contrary to the quinolone resistance phenotypes which were consistently observable among organisms withoqxAB-harboring plasmids, chromosomaloqxABelements generally did not confer quinolone resistance, except forK. pneumoniaestrains, which exhibited a typicaloqxAB-mediated phenotype characterized by cross-resistance to olaquindox, chloramphenicol, and the quinolones. Gene expression analysis illustrated that such phenotypes were due to elevated expression of the chromosomaloqxABoperon. Furthermore, transposition of theoqxABoperon from the bacterial chromosome to plasmids was found to result in a >80-fold increase in the level of expression of the OqxAB pump, confirming its status as the first constitutively expressed efflux system located in bacterial mobile elements.

scholarly journals In VitroAntibacterial Activity of AZD0914, a New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-Positive, Fastidious Gram-Negative, and Atypical Bacteria

2014 ◽  
Vol 59 (1) ◽  
pp. 467-474 ◽  
Author(s):  
Michael D. Huband ◽  
Patricia A. Bradford ◽  
Linda G. Otterson ◽  
Gregory S. Basarab ◽  
Amy C. Kutschke ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Legionella Pneumophila ◽  
Bacterial Species ◽  
Dna Gyrase ◽  
Cross Resistance ◽  
Gram Positive ◽  
Gram Negative ◽  
Content Type ◽  
Topoisomerase Inhibitor

ABSTRACTAZD0914 is a new spiropyrimidinetrione bacterial DNA gyrase/topoisomerase inhibitor with potentin vitroantibacterial activity against key Gram-positive (Staphylococcus aureus,Staphylococcus epidermidis,Streptococcus pneumoniae,Streptococcus pyogenes, andStreptococcus agalactiae), fastidious Gram-negative (Haemophilus influenzaeandNeisseria gonorrhoeae), atypical (Legionella pneumophila), and anaerobic (Clostridium difficile) bacterial species, including isolates with known resistance to fluoroquinolones. AZD0914 works via inhibition of DNA biosynthesis and accumulation of double-strand cleavages; this mechanism of inhibition differs from those of other marketed antibacterial compounds. AZD0914 stabilizes and arrests the cleaved covalent complex of gyrase with double-strand broken DNA under permissive conditions and thus blocks religation of the double-strand cleaved DNA to form fused circular DNA. Whereas this mechanism is similar to that seen with fluoroquinolones, it is mechanistically distinct. AZD0914 exhibited low frequencies of spontaneous resistance inS. aureus, and if mutants were obtained, the mutations mapped togyrB. Additionally, no cross-resistance was observed for AZD0914 against recent bacterial clinical isolates demonstrating resistance to fluoroquinolones or other drug classes, including macrolides, β-lactams, glycopeptides, and oxazolidinones. AZD0914 was bactericidal in both minimum bactericidal concentration andin vitrotime-kill studies. Inin vitrocheckerboard/synergy testing with 17 comparator antibacterials, only additivity/indifference was observed. The potentin vitroantibacterial activity (including activity against fluoroquinolone-resistant isolates), low frequency of resistance, lack of cross-resistance, and bactericidal activity of AZD0914 support its continued development.

scholarly journals Prevalence of Ciprofloxacin Resistance Among Gram-Negative Bacilli at a Specialist Hospital in Saudi Arabia

2012 ◽  
Vol 11 (4) ◽  
pp. 317-321
Author(s):  
Shamweel Ahmad
Keyword(s):  
Bacterial Species ◽  
Treatment Options ◽  
Medical Science ◽  
Surrogate Marker ◽  
Quinolone Resistance ◽  
Cross Resistance ◽  
Multi Drug Resistance ◽  
Gram Negative ◽  
Ciprofloxacin Resistance ◽  
Tract Infections

Background: Resistance to antimicrobials of different structural classes including fluoroquinolones has arisen in a multitude of bacterial species both in the community and the hospitals. This may complicate the therapeutic management of infections. Decreased susceptibility to fluoroquinolones arises mainly by singlestep mutations in the gyrA and parC genes, which encode the fluoroquinolones targets, the topoisomerase enzymes, conferring cross resistance to all fluoroquinolones. Accumulation of multiple mutations in several genes confers increasing level of resistance associated with clinical failure. However, even low level resistance can generate therapeutic failure. In 1998, some mobile elements with a potential for the horizontal transfer of the quinolone resistance genes were described. The loci which are responsible for this plasmid-mediated quinolone resistance, which have been designated as qnrA, qnrB and qnrS, have been identified in the Enterobacteriaceae species. Aim: To evaluate the susceptibility pattern of the isolates to various antibiotics and to know the prevalence rate of ciprofloxacin resistance in our hospital. Materials & Methods: A total of 916 gram-negative bacilli (GNB) were isolated from different clinical specimens over a period of nine months, were subjected to antibiotic susceptibility testing. Isolates with resistance or with a decreased susceptibility to ciprofloxacin (£20 mm) were then screened for their minimum inhibitory concentration(MIC) by using the E-test. Results: Out of 916 GNB, 321 (35%) isolates were resistant to ciprofloxacin. The MIC of these isolates ranged from 4 to >32?g/ml.Conclusion: The resistance rate to ciprofloxacin was 35% in our study. Most of the ciprofloxacin resistant isolates were from urinary tract infections (UTI). The ciprofloxacin resistance was also closely associated with multi-drug resistance, thus limiting the treatment options. Ciprofloxacin resistance can be used as a general surrogate marker of multidrug resistance, thus limiting the already restricted treatment options. The considerably high MIC values for ciprofloxacin in this study reflected the extent of the treatment problems for these resistant isolates and a need for the continuous evaluation of the commonly used antibiotics. DOI: http://dx.doi.org/10.3329/bjms.v11i4.12604 Bangladesh Journal of Medical Science Vol. 11 No. 04 Oct’12

scholarly journals In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Akinobu Ito ◽  
Takafumi Sato ◽  
Merime Ota ◽  
Miki Takemura ◽  
Toru Nishikawa ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Bacterial Species ◽  
Antibacterial Properties ◽  
Penicillin Binding Protein ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Resistant Strains ◽  
Antibacterial Spectrum

ABSTRACT Cefiderocol (CFDC; S-649266), a novel parenteral siderophore cephalosporin conjugated with a catechol moiety, has a characteristic antibacterial spectrum with a potent activity against a broad range of aerobic Gram-negative bacterial species, including carbapenem-resistant strains of Enterobacteriaceae and nonfermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol has affinity mainly for penicillin-binding protein 3 (PBP3) of Enterobacteriaceae and nonfermenting bacteria similar to that of ceftazidime. A deficiency of the iron transporter PiuA in P. aeruginosa or both CirA and Fiu in Escherichia coli caused 16-fold increases in cefiderocol MICs, suggesting that these iron transporters contribute to the permeation of cefiderocol across the outer membrane. The deficiency of OmpK35/36 in Klebsiella pneumoniae and the overproduction of efflux pump MexA-MexB-OprM in P. aeruginosa showed no significant impact on the activity of cefiderocol.

scholarly journals Mechanisms of Increased Resistance to Chlorhexidine and Cross-Resistance to Colistin following Exposure of Klebsiella pneumoniae Clinical Isolates to Chlorhexidine

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Matthew E. Wand ◽  
Lucy J. Bock ◽  
Laura C. Bonney ◽  
J. Mark Sutton
Keyword(s):  
Klebsiella Pneumoniae ◽  
Efflux Pump ◽  
Opportunistic Pathogen ◽  
Major Facilitator Superfamily ◽  
Cross Resistance ◽  
Wild Type ◽  
Content Type ◽  
Mutant Strains ◽  
Elevated Expression ◽  
Major Facilitator

ABSTRACT Klebsiella pneumoniae is an opportunistic pathogen that is often difficult to treat due to its multidrug resistance (MDR). We have previously shown that K. pneumoniae strains are able to “adapt” (become more resistant) to the widely used bisbiguanide antiseptic chlorhexidine. Here, we investigated the mechanisms responsible for and the phenotypic consequences of chlorhexidine adaptation, with particular reference to antibiotic cross-resistance. In five of six strains, adaptation to chlorhexidine also led to resistance to the last-resort antibiotic colistin. Here, we show that chlorhexidine adaptation is associated with mutations in the two-component regulator phoPQ and a putative Tet repressor gene (smvR) adjacent to the major facilitator superfamily (MFS) efflux pump gene, smvA. Upregulation of smvA (10- to 27-fold) was confirmed in smvR mutant strains, and this effect and the associated phenotype were suppressed when a wild-type copy of smvR was introduced on plasmid pACYC. Upregulation of phoPQ (5- to 15-fold) and phoPQ-regulated genes, pmrD (6- to 19-fold) and pmrK (18- to 64-fold), was confirmed in phoPQ mutant strains. In contrast, adaptation of K. pneumoniae to colistin did not result in increased chlorhexidine resistance despite the presence of mutations in phoQ and elevated phoPQ, pmrD, and pmrK transcript levels. Insertion of a plasmid containing phoPQ from chlorhexidine-adapted strains into wild-type K. pneumoniae resulted in elevated expression levels of phoPQ, pmrD, and pmrK and increased resistance to colistin, but not chlorhexidine. The potential risk of colistin resistance emerging in K. pneumoniae as a consequence of exposure to chlorhexidine has important clinical implications for infection prevention procedures.

scholarly journals Mutation ofRv2887, amarR-Like Gene, Confers Mycobacterium tuberculosis Resistance to an Imidazopyridine-Based Agent

2015 ◽  
Vol 59 (11) ◽  
pp. 6873-6881 ◽  
Author(s):  
Kathryn Winglee ◽  
Shichun Lun ◽  
Marco Pieroni ◽  
Alan Kozikowski ◽  
William Bishai
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Efflux Pump ◽  
Transcriptional Regulator ◽  
Cross Resistance ◽  
Loss Of Function ◽  
Strong Activity ◽  
Content Type ◽  
Novel Drug

ABSTRACTDrug resistance is a major problem inMycobacterium tuberculosiscontrol, and it is critical to identify novel drug targets and new antimycobacterial compounds. We have previously identified an imidazo[1,2-a]pyridine-4-carbonitrile-based agent, MP-III-71, with strong activity againstM. tuberculosis. In this study, we evaluated mechanisms of resistance to MP-III-71. We derived three independentM. tuberculosismutants resistant to MP-III-71 and conducted whole-genome sequencing of these mutants. Loss-of-function mutations inRv2887were common to all three MP-III-71-resistant mutants, and we confirmed the role ofRv2887as a gene required for MP-III-71 susceptibility using complementation. The Rv2887 protein was previously unannotated, but domain and homology analyses suggested it to be a transcriptional regulator in the MarR (multiple antibiotic resistance repressor) family, a group of proteins first identified inEscherichia colito negatively regulate efflux pumps and other mechanisms of multidrug resistance. We found that two efflux pump inhibitors, verapamil and chlorpromazine, potentiate the action of MP-III-71 and that mutation ofRv2887abrogates their activity. We also used transcriptome sequencing (RNA-seq) to identify genes which are differentially expressed in the presence and absence of a functional Rv2887 protein. We found that genes involved in benzoquinone and menaquinone biosynthesis were repressed by functional Rv2887. Thus, inactivating mutations ofRv2887, encoding a putative MarR-like transcriptional regulator, confer resistance to MP-III-71, an effective antimycobacterial compound that shows no cross-resistance to existing antituberculosis drugs. The mechanism of resistance ofM. tuberculosisRv2887mutants may involve efflux pump upregulation and also drug methylation.

Nocardiopsis coralli sp. nov. a novel actinobacterium isolated from the coral Galaxea astreata

2021 ◽  
Vol 71 (6) ◽  
Author(s):  
Fenfa Li ◽  
Qingyi Xie ◽  
Shuangqing Zhou ◽  
Fandong Kong ◽  
Yun Xu ◽  
...  
Keyword(s):  
Type Strain ◽  
Type Species ◽  
Sequence Similarity ◽  
Phylogenetic Analyses ◽  
Diaminopimelic Acid ◽  
Rrna Gene ◽  
Phenotypic Characteristics ◽  
Content Type ◽  
Link Type ◽  
Phosphatidylinositol Mannosides

Strain HNM0947T, representing a novel actinobacterium, was isolated from the coral Galaxea astreata collected from the coast of Wenchang, Hainan, China. The strain was found to have morphological and chemotaxonomic characteristics consistent with the genus Nocardiopsis . The organism formed abundant fragmented substrate mycelia and aerial mycelia which differentiated into non-motile, rod-shaped spores. Whole-cell hydrolysates contained meso-diaminopimelic acid and no diagnostic sugars. The major menaquinones were MK-10(H8), MK-10(H6) and MK-10(H4). The major phospholipids were phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannosides. The major fatty acids were iso-C16:0, anteiso-C17:0, C18:0, C18:0 10-methyl (TBSA) and anteiso-C15:0. The G+C content was 71.3 mol%. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain HNM0947T belonged to the genus Nocardiopsis and shared highest sequence similarity to Nocardiopsis salina YIM 90010T (98.8%), Nocardiopsis xinjiangensis YIM 90004T(98.5%) and Nocardiopsis kunsanensis DSM 44524T (98.3%). The strain HNM0947T was distinguished from its closest type strain by low average nucleotide identity (90.8%) and dDDH values (60.4%) respectively. Based on genotypic, chemotaxonomic and phenotypic characteristics, it was concluded that strain HNM0947T represents a novel species of the genus Nocardiopsis whose name was proposed as Nocardiopsis coralli sp. nov. The type strain was HNM0947T (=CCTCC AA 2020015 T=KCTC 49525 T).

scholarly journals Biocidal Agents Used for Disinfection Can Enhance Antibiotic Resistance in Gram-Negative Species

Antibiotics ◽  
2018 ◽  
Vol 7 (4) ◽  
pp. 110 ◽  
Author(s):  
Günter Kampf
Keyword(s):  
Antibiotic Resistance ◽  
Efflux Pump ◽  
Health Benefit ◽  
Cross Resistance ◽  
Gram Negative ◽  
Medline Search ◽  
Resistance To Antibiotics ◽  
Didecyldimethylammonium Chloride ◽  
Healthcare Associated ◽  
Sublethal Concentrations

Biocidal agents used for disinfection are usually not suspected to enhance cross-resistance to antibiotics. The aim of this review was therefore to evaluate the effect of 13 biocidal agents at sublethal concentrations on antibiotic resistance in Gram-negative species. A medline search was performed for each biocidal agent on antibiotic tolerance, antibiotic resistance, horizontal gene transfer, and efflux pump. In cells adapted to benzalkonium chloride a new resistance was most frequently found to ampicillin (eight species), cefotaxime (six species), and sulfamethoxazole (three species), some of them with relevance for healthcare-associated infections such as Enterobacter cloacae or Escherichia coli. With chlorhexidine a new resistance was often found to ceftazidime, sulfamethoxazole and imipenem (eight species each) as well as cefotaxime and tetracycline (seven species each). Cross-resistance to antibiotics was also found with triclosan, octenidine, sodium hypochlorite, and didecyldimethylammonium chloride. No cross-resistance to antibiotics has been described after low level exposure to ethanol, propanol, peracetic acid, polyhexanide, povidone iodine, glutaraldehyde, and hydrogen peroxide. Taking into account that some biocidal agents used in disinfectants have no health benefit (e.g., in alcohol-based hand rubs) but may cause antibiotic resistance it is obvious to prefer products without them.

scholarly journals Transcriptional Profiling Analysis of the Global Regulator NorG, a GntR-Like Protein of Staphylococcus aureus

2011 ◽  
Vol 193 (22) ◽  
pp. 6207-6214 ◽  
Author(s):  
Q. C. Truong-Bolduc ◽  
P. M. Dunman ◽  
T. Eidem ◽  
D. C. Hooper
Keyword(s):  
Staphylococcus Aureus ◽  
Target Genes ◽  
Efflux Pump ◽  
Transcriptional Profiling ◽  
Fold Increase ◽  
Regulatory Function ◽  
Drug Transporter ◽  
Content Type ◽  
Global Regulators ◽  
Inorganic Ion

The GntR-like protein NorG has been shown to affectStaphylococcus aureusgenes involved in resistance to quinolones and β-lactams, such as those encoding the NorB and AbcA transporters. To identify the target genes regulated by NorG, we carried out transcriptional-profiling assays usingS. aureusRN6390 and its isogenicnorG::catmutant. Our data showed that NorG positively affected the transcription of global regulatorsmgrA,arlS, andsarZ. The three putative drug efflux pump genes most positively affected by NorG were the NorB efflux pump (5.1-fold), the MmpL-like protein SACOL2566 (5.2-fold), and the BcrA-like drug transporter SACOL2525 (5.7-fold) genes. TheS. aureuspredicted MmpL protein showed 53% homology with the MmpL lipid transporter ofMycobacterium tuberculosis, and the putative SACOL2525 protein showed 87% homology with the bacitracin drug transporter BcrA ofStaphylococcus hominis. Two pump genes most negatively affected by NorG were the NorC (4-fold) and AbcA (6-fold) genes. Other categories of genes, such as those participating in amino acid, inorganic ion, or nucleotide transporters and metabolism, were also affected by NorG. Real-time reverse transcription (RT)-PCR assays formgrA,arlS,sarZ,norB,norC,abcA,mmpL, andbcrA-like were carried out to verify microarray data and showed the same level of up- or downregulation by NorG. ThenorGmutant showed a 2-fold increase in resistance to norfloxacin and rhodamine, both substrates of the NorC transporter, which is consistent with the resistance phenotype conferred by overexpression ofnorCon a plasmid. These data indicate that NorG has broad regulatory function inS. aureus.

scholarly journals An alkylaminoquinazoline restores antibiotic activity in Gram-negative resistant isolates

Microbiology ◽  
2011 ◽  
Vol 157 (2) ◽  
pp. 566-571 ◽  
Author(s):  
Abdallah Mahamoud ◽  
Jacqueline Chevalier ◽  
Milad Baitiche ◽  
Elissavet Adam ◽  
Jean-Marie Pagès
Keyword(s):  
Efflux Pump ◽  
Bacterial Species ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Side Chain ◽  
Structural Class ◽  
Gram Negative ◽  
Activity Spectrum ◽  
Efflux Pump Inhibitors ◽  
Drug Efflux Pump

To date, various bacterial drug efflux pump inhibitors (EPIs) have been described. They exhibit variability in their activity spectrum with respect to antibiotic structural class and bacterial species. Among the various 4-alkylaminoquinazoline derivatives synthesized and studied in this work, one molecule, 1167, increased the susceptibility of important human-pathogenic, resistant, Gram-negative bacteria towards different antibiotic classes. This 4-(3-morpholinopropylamino)-quinazoline induced an increase in the activity of chloramphenicol, nalidixic acid, norfloxacin and sparfloxacin, which are substrates of the AcrAB-TolC and MexAB-OprM efflux pumps that act in these multidrug-resistant isolates. In addition, 1167 increased the intracellular concentration of chloramphenicol in efflux pump-overproducing strains. The rate of restoration depended on the structure of the antibiotic, suggesting that different sites in the efflux pumps may be involved. A molecule exhibiting a morpholine functional group and a propyl extension of the side chain was more active.

scholarly journals The Novel Kasugamycin 2′-N-Acetyltransferase Geneaac(2′)-IIa, Carried by the IncP Island, Confers Kasugamycin Resistance to Rice-Pathogenic Bacteria

2012 ◽  
Vol 78 (16) ◽  
pp. 5555-5564 ◽  
Author(s):  
Atsushi Yoshii ◽  
Hiromitsu Moriyama ◽  
Toshiyuki Fukuhara
Keyword(s):  
Gene Transfer ◽  
Pathogenic Bacteria ◽  
Magnaporthe Grisea ◽  
Bacterial Species ◽  
Aminoglycoside Antibiotic ◽  
Effective Control ◽  
Cross Resistance ◽  
Burkholderia Glumae ◽  
Content Type ◽  
Brown Stripe

ABSTRACTKasugamycin (KSM), a unique aminoglycoside antibiotic, has been used in agriculture for many years to control not only rice blast caused by the fungusMagnaporthe griseabut also rice bacterial grain and seedling rot or rice bacterial brown stripe caused byBurkholderia glumaeorAcidovorax avenaesubsp.avenae, respectively. Since both bacterial pathogens are seed-borne and cause serious injury to rice seedlings, the emergence of KSM-resistantB. glumaeandA. avenaeisolates highlights the urgent need to understand the mechanism of resistance to KSM. Here, we identified a novel gene,aac(2′)-IIa, encoding a KSM 2′-N-acetyltransferase from both KSM-resistant pathogens but not from KSM-sensitive bacteria. AAC(2′)-IIa inactivates KSM, although it reveals no cross-resistance to other aminoglycosides. Theaac(2′)-IIagene fromB. glumaestrain 5091 was identified within the IncP genomic island inserted into the bacterial chromosome, indicating the acquisition of this gene by horizontal gene transfer. Although excision activity of the IncP island and conjugational gene transfer was not detected under the conditions tested, circular intermediates containing theaac(2′)-IIagene were detected. These results indicate that theaac(2′)-IIagene had been integrated into the IncP island of a donor bacterial species. Molecular detection of theaac(2′)-IIagene could distinguish whether isolates are resistant or susceptible to KSM. This may contribute to the production of uninfected rice seeds and lead to the effective control of these pathogens by KSM.

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