scholarly journals Accociation between molecular mechanisms of antimicrobial resistance, pnenotypes and serotypes in Streptococcus pneumoniae

2019 ◽  
Vol 16 (4) ◽  
pp. 454-467
Author(s):  
A. V. Davydov ◽  
L. P. Titov ◽  
A. N. Kharkhal ◽  
V. G. Baraulya ◽  
Y. V. Gusakova
Keyword(s):  
Antimicrobial Resistance ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Pneumococcal Infection ◽  
Acute Otitis Media ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Penicillin Binding Proteins ◽  
Epidemiological Features ◽  
Resistant Strains

Studies on pneumococcal resistome and molecular antimicrobial resistance mechanisms are relevant and may be used in large-scale epidemiological researches and surveillance of antimicrobial resistance.A study of antimicrobial molecular resistance in the pneumococcal strains, that were isolated from the patients having the different forms of the pneumococcal infection or carriage, and association of it with phenotypes, clinical and epidemiological features of the strains (serotype, form of the infection).We studied 546 pneumococcal strains and 5 specimens, that were isolated/obtained from the patients of various age (5 days – 81 years) having the different forms of the pneumococcal infection (meningitis and other invasive forms – 28, pneumonia – 27, acute rhinosinusitis – 18, acute otitis media – 118, conjunctivitis – 26) or carriage (331).We used multiplex PCR to detect the following molecular pneumococcal antimicrobial resistance determinants – genes mefA, ermB and mutations in the penicillin-binding proteins: pbp1a (574T→N, 575S→T, 576Q→G and 577F→Y); pbp2b (431T→K, 432Q→L) and pbp2x (338T→A).Among studied strains 60 % of 551 possess at least one resistance mechanism to macrolides/lincosamides, while 22 % were heteroresistant (mefA + ermB). About 65 % of the strains carry at least one pbp modification, 26 % – two modifications and 24 % – three pbp modifications. 23S RNA methylase (ermB gene) were discovered as a dominating mechanism and was detected in 43 % of genetically resistant strains. Pbp 1a + 2x + 2b and pbp 1a + 2x were more frequent modifications among penicillin genetically resistant pneumococci, while pbp2b genotype was not detected.

scholarly journals Phenotypic and molecular characterization of antimicrobial resistance in Proteus mirabilis isolates from dogs

2014 ◽  
Vol 63 (11) ◽  
pp. 1561-1567 ◽  
Author(s):  
Kazuki Harada ◽  
Ayaka Niina ◽  
Takae Shimizu ◽  
Yujiro Mukai ◽  
Ken Kuwajima ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Proteus Mirabilis ◽  
Large Scale ◽  
Antimicrobial Agents ◽  
Companion Animals ◽  
Resistance Mechanisms ◽  
Quinolone Resistance ◽  
Class 1 ◽  
Resistant Strains

Large-scale monitoring of resistance to 14 antimicrobial agents was performed using 103 Proteus mirabilis strains isolated from dogs in Japan. Resistant strains were analysed to identify their resistance mechanisms. Rates of resistance to chloramphenicol, streptomycin, enrofloxacin, trimethoprim/sulfamethoxazole, kanamycin, ampicillin, ciprofloxacin, cephalothin, gentamicin, cefoxitin and cefotaxime were 20.4, 15.5, 12.6, 10.7, 9.7, 8.7, 5.8, 2.9, 2.9, 1.9 and 1.9 %, respectively. No resistance to ceftazidime, aztreonam or imipenem was found. Class 1 and 2 integrases were detected in 2.9 and 11.7 % of isolates, respectively. Class 1 integrons contained aadB or aadB–catB-like-blaOXA10 –aadA1, whereas those of class 2 contained sat–aadA1, dhfr1–sat–aadA1 or none of the anticipated resistance genes. Of five distinct plasmid-mediated quinolone-resistance (PMQR) genes, only qnrD gene was detected in 1.9 % of isolates. Quinolone-resistance determining regions (QRDRs) of gyrA and parC from 13 enrofloxacin-intermediate and -resistant isolates were sequenced. Seven strains had double mutations and three had single mutations. Three of nine ampicillin-resistant isolates harboured AmpC-type β-lactamases (i.e. bla CMY-2, bla CMY-4 and bla DHA-1). These results suggest that canine Proteus mirabilis deserves continued surveillance as an important reservoir of antimicrobial resistance determinants. This is the first report, to our knowledge, describing integrons, PMQRs and QRDR mutations in Proteus mirabilis isolates from companion animals.

scholarly journals Antimicrobial Resistance in Oral biofilm: Challenges and Alternatives

2021 ◽  
Vol 12 (1) ◽  
pp. 349-356
Author(s):  
Satish Kumar Sharma ◽  
Shmmon Ahmad
Keyword(s):  
Antimicrobial Resistance ◽  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Resistance Mechanisms ◽  
Bacterial Biofilm ◽  
Bacterial Biofilms ◽  
Target Cells ◽  
Bacterial Cells ◽  
Antimicrobial Drugs ◽  
Oral Infections

Bacterial biofilm has been a major contributor to severe bacterial infections in humans. Oral infections have also been associated with biofilm-forming microbes. Several antimicrobial strategies have been developed to combat bacterial biofilms. However, the complexity of the oral cavity has made it difficult to use common drug treatments. Most effective ways to control normal bacterial infections are rendered ineffective for bacterial biofilms. Due to limited drug concentration availability, drug neutralization or altered phenotype of bacterial cells, different drug have been ineffective to identify the target cells. This leads to the development of the multifaceted phenomenon of antimicrobial resistance (AMR). Biofilm research done so far has been focused on using antimicrobial drugs to target molecular mechanisms of cells. The severity and resistance mechanisms of extracellular matrix (ECM) have been underestimated. The present study describes different antimicrobial strategies with respect to their applications in dental or oral infections. A prospective strategy has been proposed targeting ECM which is expected to provide an insight on biofilm obstinacy and antimicrobial resistance.

scholarly journals Advanced Resistance Studies Identify Two Discrete Mechanisms in Staphylococcus aureus to Overcome Antibacterial Compounds that Target Biotin Protein Ligase

Antibiotics ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 165 ◽  
Author(s):  
Andrew J. Hayes ◽  
Jiulia Satiaputra ◽  
Louise M. Sternicki ◽  
Ashleigh S. Paparella ◽  
Zikai Feng ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Transcriptional Repression ◽  
Molecular Mechanisms ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Resistance Rate ◽  
Biotin Protein Ligase ◽  
Essential Enzyme

Biotin protein ligase (BPL) inhibitors are a novel class of antibacterial that target clinically important methicillin-resistant Staphylococcus aureus (S. aureus). In S. aureus, BPL is a bifunctional protein responsible for enzymatic biotinylation of two biotin-dependent enzymes, as well as serving as a transcriptional repressor that controls biotin synthesis and import. In this report, we investigate the mechanisms of action and resistance for a potent anti-BPL, an antibacterial compound, biotinyl-acylsulfamide adenosine (BASA). We show that BASA acts by both inhibiting the enzymatic activity of BPL in vitro, as well as functioning as a transcription co-repressor. A low spontaneous resistance rate was measured for the compound (<10−9) and whole-genome sequencing of strains evolved during serial passaging in the presence of BASA identified two discrete resistance mechanisms. In the first, deletion of the biotin-dependent enzyme pyruvate carboxylase is proposed to prioritize the utilization of bioavailable biotin for the essential enzyme acetyl-CoA carboxylase. In the second, a D200E missense mutation in BPL reduced DNA binding in vitro and transcriptional repression in vivo. We propose that this second resistance mechanism promotes bioavailability of biotin by derepressing its synthesis and import, such that free biotin may outcompete the inhibitor for binding BPL. This study provides new insights into the molecular mechanisms governing antibacterial activity and resistance of BPL inhibitors in S. aureus.

scholarly journals Evaluation of different phenotypic tests for detection of metallo-β-lactamases in imipenem-resistant Pseudomonas aeruginosa

2017 ◽  
Vol 9 (04) ◽  
pp. 249-253 ◽  
Author(s):  
Rohit Sachdeva ◽  
Babita Sharma ◽  
Rajni Sharma
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Large Scale ◽  
Wide Spectrum ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Clinical Samples ◽  
Resistant Strains ◽  
Synergy Test ◽  
Phenotypic Tests ◽  
Simple Screening

Abstract PURPOSE: Pseudomonas aeruginosa causes a wide spectrum of infections including bacteremia, pneumonia, urinary tract infection, etc., Metallo-beta-lactamase (MBL) producing P. aeruginosa is an emerging threat and cause of concern as they have emerged as one of the most feared resistance mechanisms. This study was designed to know the prevalence of MBL production in P. aeruginosa and to evaluate the four phenotypic tests for detection of MBL production in imipenem-resistant clinical isolates of P. aeruginosa. METHODS: Totally, 800 isolates of P. aeruginosa isolated from various clinical samples were evaluated for carbapenem resistance and MBL production. All imipenem-resistant strains were tested for carabapenemase production by modified Hodge test. Screening for MBL production was done by double-disc synergy test and combined disc test (CDT). Confirmation of MBL production was done by the E-test (Ab BioDisk, Solna, Sweden). RESULTS: Out of the 800 isolates of P. aeruginosa, 250 isolates were found resistant to imipenem. Based on the results of E-test, 147 (18.37%) isolates of P. aeruginosa were positive for MBL production. The CDT has the highest sensitivity and specificity for the detection of MBL production as compared to other tests. CONCLUSION: The results of this study are indicative that MBL production is an important mechanism of carbapenem resistance among P. aeruginosa. Use of simple screening test like CDT will be crucial step toward large-scale monitoring of these emerging resistant determinants. Phenotypic test for MBL production has to be standardized, and all the isolates should be routinely screened for MBL production.

scholarly journals Struggle To Survive: the Choir of Target Alteration, Hydrolyzing Enzyme, and Plasmid Expression as a Novel Aztreonam-Avibactam Resistance Mechanism

mSystems ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Ke Ma ◽  
Yu Feng ◽  
Alan McNally ◽  
Zhiyong Zong
Keyword(s):  
Antimicrobial Resistance ◽  
Antisense Rna ◽  
Antimicrobial Agents ◽  
Binding Protein ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Penicillin Binding Protein ◽  
Plasmid Copy ◽  
Copy Numbers

ABSTRACT Aztreonam-avibactam is a promising antimicrobial combination against multidrug-resistant organisms, such as carbapenemase-producing Enterobacterales. Resistance to aztreonam-avibactam has been found, but the resistance mechanism remains poorly studied. We recovered three Escherichia coli isolates of an almost identical genome but exhibiting varied aztreonam-avibactam resistance. The isolates carried a cephalosporinase gene, blaCMY-42, on IncIγ plasmids with a single-nucleotide variation in an antisense RNA-encoding gene, inc, of the replicon. The isolates also had four extra amino acids (YRIK) in penicillin-binding protein 3 (PBP3) due to a duplication of a 12-nucleotide (TATCGAATTAAC) stretch in pbp3. By cloning and plasmid-curing experiments, we found that elevated CMY-42 cephalosporinase production or amino acid insertions in PBP3 alone mediated slightly reduced susceptibility to aztreonam-avibactam, but their combination conferred aztreonam-avibactam resistance. We show that the elevated CMY-42 production results from increased plasmid copy numbers due to mutations in inc. We also verified the findings using in vitro mutation assays, in which aztreonam-avibactam-resistant mutants also had mutations in inc and elevated CMY-42 production compared with the parental strain. This choir of target modification, hydrolyzing enzyme, and plasmid expression represents a novel, coordinated, complex antimicrobial resistance mechanism and also reflects the struggle of bacteria to survive under selection pressure imposed by antimicrobial agents. IMPORTANCE Carbapenemase-producing Enterobacterales (CPE) is a serious global challenge with limited therapeutic options. Aztreonam-avibactam is a promising antimicrobial combination with activity against CPE producing serine-based carbapenemases and metallo-β-lactamases and has the potential to be a major option for combatting CPE. Aztreonam-avibactam resistance has been found, but resistance mechanisms remain largely unknown. Understanding resistance mechanisms is essential for optimizing treatment and developing alternative therapies. Here, we found that either penicillin-binding protein 3 modification or the elevated expression of cephalosporinase CMY-42 due to increased plasmid copy numbers does not confer resistance to aztreonam-avibactam, but their combination does. We demonstrate that increased plasmid copy numbers result from mutations in antisense RNA-encoding inc of the IncIγ replicon. The findings reveal that antimicrobial resistance may be due to concerted combinatorial effects of target alteration, hydrolyzing enzyme, and plasmid expression and also highlight that resistance to any antimicrobial combination will inevitably emerge.

scholarly journals Development and Persistence of Antimicrobial Resistance in Pseudomonas aeruginosa: a Longitudinal Observation in Mechanically Ventilated Patients

2007 ◽  
Vol 51 (4) ◽  
pp. 1341-1350 ◽  
Author(s):  
Anita Reinhardt ◽  
Thilo Köhler ◽  
Paul Wood ◽  
Peter Rohner ◽  
Jean-Luc Dumas ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Resistance ◽  
Selective Pressure ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Antimicrobial Treatment ◽  
Aminoglycoside Resistance ◽  
Prolonged Intubation ◽  
Treatment Regimens ◽  
Underlying Mechanisms

ABSTRACT Intubated patients frequently become colonized by Pseudomonas aeruginosa, which is subsequently responsible for ventilator-associated pneumonia. This pathogen readily acquires resistance against available antimicrobials. Depending on the resistance mechanism selected for, resistance might either be lost or persist after removal of the selective pressure. We investigated the rapidity of selection, as well as the persistence, of antimicrobial resistance and determined the underlying mechanisms. We selected 109 prospectively collected P. aeruginosa tracheal isolates from two patients based on their prolonged intubation and colonization periods, during which they had received carbapenem, fluoroquinolone (FQ), or combined β-lactam-aminoglycoside therapies. We determined antimicrobial resistance phenotypes by susceptibility testing and used quantitative real-time PCR to measure the expression of resistance determinants. Within 10 days after the initiation of therapy, all treatment regimens selected resistant isolates. Resistance to β-lactam and FQ was correlated with ampC and mexC gene expression levels, respectively, whereas imipenem resistance was attributable to decreased oprD expression. Combined β-lactam-aminoglycoside resistance was associated with the appearance of small-colony variants. Imipenem and FQ resistance persisted for prolonged times once the selecting antimicrobial treatment had been discontinued. In contrast, resistance to β-lactams disappeared rapidly after removal of the selective pressure, to reappear promptly upon renewed exposure. Our results suggest that resistant P. aeruginosa is selected in less than 10 days independently of the antimicrobial class. Different resistance mechanisms lead to the loss or persistence of resistance after the removal of the selecting agent. Even if resistant isolates are not evident upon culture, they may persist in the lung and can be rapidly reselected.

scholarly journals A systemic study of indoxacarb resistance in Spodoptera litura revealed complex expression profiles and regulatory mechanism

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Li Shi ◽  
Yao Shi ◽  
Ya Zhang ◽  
Xiaolan Liao
Keyword(s):  
Spodoptera Litura ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Expression Profiles ◽  
Resistance Mechanisms ◽  
Differentially Expressed ◽  
Glutathione S Transferase ◽  
Differentially Expressed Mirnas ◽  
Important Pest ◽  
Resistant Strains

Abstract The tobacco cutworm, Spodoptera litura, is an important pest of crop and vegetable plants worldwide, and its resistance to insecticides have quickly developed. However, the resistance mechanisms of this pest are still unclear. In this study, the change in mRNA and miRNA profiles in the susceptible, indoxacarb-resistant and field indoxacarb-resistant strains of S. litura were characterized. Nine hundred and ten co-up-regulated and 737 co-down-regulated genes were identified in the resistant strains. Further analysis showed that 126 co-differentially expressed genes (co-DEGs) (cytochrome P450, carboxy/cholinesterase, glutathione S-transferase, ATP-binding cassette transporter, UDP-glucuronosyl transferase, aminopeptidase N, sialin, serine protease and cuticle protein) may play important roles in indoxacarb resistance in S. litura. In addition, a total of 91 known and 52 novel miRNAs were identified, and 10 miRNAs were co-differentially expressed in the resistant strains of S. litura. Furthermore, 10 co-differentially expressed miRNAs (co-DEmiRNAs) had predicted co-DEGs according to the expected miRNA-mRNA negative regulation pattern and 37 indoxacarb resistance-related co-DEGs were predicted to be the target genes. These results not only broadened our understanding of molecular mechanisms of insecticide resistance by revealing complicated profiles, but also provide important clues for further study on the mechanisms of miRNAs involved in indoxacarb resistance in S. litura.

Molecular Basis Explanation of Imatinib Resistance of Bcr-Abl Due to T315I and P-Loop Mutations from Molecular Dynamics Simulations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2917-2917
Author(s):  
Tai-Sung Lee ◽  
Steven Potts ◽  
Hagop Kantarjian ◽  
Jorge Cortes ◽  
Francis Giles ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Electrostatic Interactions ◽  
Large Scale ◽  
Resistance Mechanism ◽  
Md Simulations ◽  
Resistance Mechanisms ◽  
Static Structure ◽  
Imatinib Resistance ◽  
Dynamics Simulations

Abstract Molecular dynamics (MD) simulations on the complex of imatinib with the wild-type, T315I, and other 10 P-loop mutants of the tyrosine kinase Bcr-Abl have been performed to study the imatinib resistance mechanism at the atomic level. MD simulations show that large scale computational simulations could offer insight information that a static structure or simple homology modeling methods cannot provide for studying the Bcr-Abl imatinib resistance problem, especially in the case of conformational changes due to remote mutations. By utilizing the Molecular Mechanics/Poisson-Boltzmann surface area (MM-PBSA) techniques and analyzing the interactions between imatinib and individual residues, imatinib resistance mechanisms not previously thought have been revealed. Non-directly contacted P-loop mutations either unfavorably change the direct electrostatic interactions with imatinib, or cause the conformational changes influencing the contact energies between imatinib and other non-P-loop residues. We demonstrate that imatinib resistance of T315I mainly comes from the breakdown of the interactions between imatinib and E286 and M290, contradictory to previously suggested that the missing hydrogen bonding is the main contribution. We also demonstrate that except for the mutations of the direct contact residues, such as L248 and Y253, the unfavorable electrostatic interaction between P-loop and imatinib is the main reason for resistance for the P-loop mutations. Furthermore, in Y255H, protonation of the histidin is essential for rendering this mutation resistant to Gleevec. Our results demonstrate that MD is a powerful way to verify and predict clinical response or resistance to imatinib and other potential drugs.

scholarly journals Pneumococcal resistance to antibiotics.

1990 ◽  
Vol 3 (2) ◽  
pp. 171-196 ◽  
Author(s):  
K P Klugman
Keyword(s):  
Molecular Mechanisms ◽  
Penicillin Resistance ◽  
Multiple Resistance ◽  
Mechanisms Of Resistance ◽  
Pneumococcal Infections ◽  
Penicillin Binding Proteins ◽  
Factors Associated ◽  
Duration Of Hospitalization ◽  
Resistant Strains ◽  
And Function

The geographic distribution of pneumococci resistant to one or more of the antibiotics penicillin, erythromycin, trimethoprim-sulfamethoxazole, and tetracycline appears to be expanding, and there exist foci of resistance to chloramphenicol and rifampin. Multiply resistant pneumococci are being encountered more commonly and are more often community acquired. Factors associated with infection caused by resistant pneumococci include young age, duration of hospitalization, infection with a pneumococcus of serogroup 6, 19, or 23 or serotype 14, and exposure to antibiotics to which the strain is resistant. At present, the most useful drugs for the management of resistant pneumococcal infections are cefotaxime, ceftriaxone, vancomycin, and rifampin. If the strains are susceptible, chloramphenicol may be useful as an alternative, less expensive agent. Appropriate interventions for the control of resistant pneumococcal outbreaks include investigation of the prevalence of resistant strains, isolation of patients, possible treatment of carriers, and reduction of usage of antibiotics to which the strain is resistant. The molecular mechanisms of penicillin resistance are related to the structure and function of penicillin-binding proteins, and the mechanisms of resistance to other agents involved in multiple resistance are being elucidated. Recognition is increasing of the standard screening procedure for penicillin resistance, using a 1-microgram oxacillin disk.

Intrinsic, adaptive and acquired antimicrobial resistance in Gram-negative bacteria

2017 ◽  
Vol 61 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Mohsen Arzanlou ◽  
Wern Chern Chai ◽  
Henrietta Venter
Keyword(s):  
Antimicrobial Resistance ◽  
Molecular Mechanisms ◽  
Resistance Mechanisms ◽  
Stress Conditions ◽  
Gram Negative Bacteria ◽  
Mechanisms Of Resistance ◽  
Intrinsic Resistance ◽  
Antimicrobial Drugs ◽  
Gram Negative ◽  
Gram Negative Organisms

Gram-negative bacteria are responsible for a large proportion of antimicrobial-resistant infections in humans and animals. Among this class of bacteria are also some of the most successful environmental organisms. Part of this success is their adaptability to a variety of different niches, their intrinsic resistance to antimicrobial drugs and their ability to rapidly acquire resistance mechanisms. These mechanisms of resistance are not exclusive and the interplay of several mechanisms causes high levels of resistance. In this review, we explore the molecular mechanisms underlying resistance in Gram-negative organisms and how these different mechanisms enable them to survive many different stress conditions.

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