scholarly journals Amidochelocardin Overcomes Resistance Mechanisms Exerted on Tetracyclines and Natural Chelocardin

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 619
Author(s):  
Fabienne Hennessen ◽  
Marcus Miethke ◽  
Nestor Zaburannyi ◽  
Maria Loose ◽  
Tadeja Lukežič ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Efflux Pump ◽  
Resistance Mechanism ◽  
Tetracycline Resistance ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistance Breaking ◽  
Pharmaceutical Properties ◽  
Tract Infections

The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on chelocardin, a member of the atypical tetracyclines, and its bioengineered derivative amidochelocardin, both showing broad-spectrum antibacterial activity within the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) panel. Further lead development of chelocardins requires extensive biological and chemical profiling to achieve favorable pharmaceutical properties and efficacy. This study shows that both molecules possess resistance-breaking properties enabling the escape from most common tetracycline resistance mechanisms. Further, we show that these compounds are potent candidates for treatment of urinary tract infections due to their in vitro activity against a large panel of multidrug-resistant uropathogenic clinical isolates. In addition, the mechanism of resistance to natural chelocardin was identified as relying on efflux processes, both in the chelocardin producer Amycolatopsis sulphurea and in the pathogen Klebsiella pneumoniae. Resistance development in Klebsiella led primarily to mutations in ramR, causing increased expression of the acrAB-tolC efflux pump. Most importantly, amidochelocardin overcomes this resistance mechanism, revealing not only the improved activity profile but also superior resistance-breaking properties of this novel antibacterial compound.

scholarly journals Plasmid-Mediated OqxAB Is an Important Mechanism for Nitrofurantoin Resistance in Escherichia coli

2015 ◽  
Vol 60 (1) ◽  
pp. 537-543 ◽  
Author(s):  
Pak-Leung Ho ◽  
Ka-Ying Ng ◽  
Wai-U Lo ◽  
Pierra Y. Law ◽  
Eileen Ling-Yi Lai ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Geometric Mean ◽  
Resistance Mechanism ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Content Type ◽  
E Coli ◽  
High Level ◽  
Tract Infections

ABSTRACTIncreasing consumption of nitrofurantoin (NIT) for treatment of acute uncomplicated urinary tract infections (UTI) highlights the need to monitor emerging NIT resistance mechanisms. This study investigated the molecular epidemiology of the multidrug-resistant efflux geneoqxABand its contribution to nitrofurantoin resistance by usingEscherichia coliisolates originating from patients with UTI (n= 205; collected in 2004 to 2013) and food-producing animals (n= 136; collected in 2012 to 2013) in Hong Kong. TheoqxABgene was highly prevalent among NIT-intermediate (11.5% to 45.5%) and -resistant (39.2% to 65.5%) isolates but rare (0% to 1.7%) among NIT-susceptible (NIT-S) isolates. In our isolates, theoqxABgene was associated with IS26and was carried by plasmids of diverse replicon types. Multilocus sequence typing revealed that the clones ofoqxAB-positiveE. coliwere diverse. The combination ofoqxABandnfsAmutations was found to be sufficient for high-level NIT resistance. Curing ofoqxAB-carrying plasmids from 20 NIT-intermediate/resistant UTI isolates markedly reduced the geometric mean MIC of NIT from 168.9 μg/ml to 34.3 μg/ml. In the plasmid-cured variants, 20% (1/5) of isolates withnfsAmutations were NIT-S, while 80% (12/15) of isolates withoutnfsAmutations were NIT-S (P= 0.015). The presence of plasmid-basedoqxABincreased the mutation prevention concentration of NIT from 128 μg/ml to 256 μg/ml and facilitated the development of clinically important levels of nitrofurantoin resistance. In conclusion, plasmid-mediatedoqxABis an important nitrofurantoin resistance mechanism. There is a great need to monitor the dissemination of this transferable multidrug-resistant efflux pump.

scholarly journals Molecular Epidemiology and Characterization of Carbapenem-Resistant Klebsiella pneumoniae Isolated from Urine at a Teaching Hospital in Taiwan

2021 ◽  
Vol 9 (2) ◽  
pp. 271
Author(s):  
Yuarn-Jang Lee ◽  
Chih-Hung Huang ◽  
Noor Andryan Ilsan ◽  
I-Hui Lee ◽  
Tzu-Wen Huang
Keyword(s):  
Klebsiella Pneumoniae ◽  
Teaching Hospital ◽  
Efflux Pump ◽  
Resistance Mechanisms ◽  
Pcr Analysis ◽  
Carbapenem Resistant ◽  
High Prevalence ◽  
Antimicrobial Susceptibility Tests ◽  
Susceptibility Tests ◽  
Tract Infections

Urinary tract infections (UTIs) are common in clinics and hospitals and are associated with a high economic burden. Enterobacterium Klebsiella pneumoniae is a prevalent agent causing UTIs. A high prevalence of carbapenem-resistant K. pneumoniae (CRKP) has emerged recently and is continuing to increase. Seventeen urinary CRKP isolates collected at a teaching hospital in Taiwan from December 2016 to September 2017 were analyzed to elucidate their drug resistance mechanisms. Two-thirds of the isolates were obtained from outpatients. Antimicrobial susceptibility tests demonstrated multidrug resistance in all the isolates. Multilocus sequence typing analysis showed high diversity among the isolates. PCR analysis demonstrated the presence of carbapenemases in three isolates. All isolates carried at least one other extended-spectrum β-lactamase, including TEM, DHA, and CTX-M. Fifteen isolates contained mutations in one of the outer membrane porins that were assessed. The expression levels of the acrB and/or oqxB efflux pump genes, as determined by qRT-PCR, were upregulated in 11 isolates. Six isolates might have utilized other efflux pumps or antimicrobial resistance mechanisms. These analyses demonstrated a highly diverse population and the presence of complex resistance mechanisms in urinary isolates of K. pneumoniae.

scholarly journals Persistent Bacteremia fromPseudomonas aeruginosawithIn VitroResistance to the Novel Antibiotics Ceftolozane-Tazobactam and Ceftazidime-Avibactam

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Louie Mar Gangcuangco ◽  
Patricia Clark ◽  
Cynthia Stewart ◽  
Goran Miljkovic ◽  
Zane K. Saul
Keyword(s):  
Susceptibility Testing ◽  
Resistance Mechanism ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Blood Cultures ◽  
The Novel ◽  
First Case ◽  
Persistent Bacteremia ◽  
Novel Antibiotics

Ceftazidime-avibactam and ceftolozane-tazobactam are new antimicrobials with activity against multidrug-resistantPseudomonas aeruginosa. We present the first case of persistentP.aeruginosabacteremia within vitroresistance to these novel antimicrobials. A 68-year-old man with newly diagnosed follicular lymphoma was admitted to the medical intensive care unit for sepsis and right lower extremity cellulitis. The patient was placed empirically on vancomycin and piperacillin-tazobactam. Blood cultures from Day 1 of hospitalization grewP.aeruginosasusceptible to piperacillin-tazobactam and cefepime identified using VITEK 2 (Biomerieux, Lenexa, KS). Repeat blood cultures from Day 5 grewP.aeruginosaresistant to all cephalosporins, as well as to meropenem by Day 10. Susceptibility testing performed by measuring minimum inhibitory concentration byE-test (Biomerieux, Lenexa, KS) revealed that blood cultures from Day 10 were resistant to ceftazidime-avibactam and ceftolozane-tazobactam. The Verigene Blood Culture-Gram-Negative (BC-GN) microarray-based assay (Nanosphere, Inc., Northbrook, IL) was used to investigate underlying resistance mechanism in theP.aeruginosaisolate but CTX-M, KPC, NDM, VIM, IMP, and OXA gene were not detected. This case report highlights the well-documented phenomenon of antimicrobial resistance development inP.aeruginosaeven during the course of appropriate antibiotic therapy. In the era of increasing multidrug-resistant organisms, routine susceptibility testing ofP. aeruginosato ceftazidime-avibactam and ceftolozane-tazobactam is warranted. Emerging resistance mechanisms to these novel antibiotics need to be further investigated.

scholarly journals IS5Element Integration, a Novel Mechanism for RapidIn VivoEmergence of Tigecycline Nonsusceptibility in Klebsiella pneumoniae

2014 ◽  
Vol 58 (10) ◽  
pp. 6151-6156 ◽  
Author(s):  
Lindsey E. Nielsen ◽  
Erik C. Snesrud ◽  
Fatma Onmus-Leone ◽  
Yoon I. Kwak ◽  
Ricardo Avilés ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Insertion Element ◽  
Content Type ◽  
Reverse Transcription Quantitative Pcr ◽  
Antimicrobial Susceptibility Tests ◽  
Susceptibility Tests

ABSTRACTTigecycline nonsusceptibility is concerning because tigecycline is increasingly relied upon to treat carbapenem- or colistin-resistant organisms. InEnterobacteriaceae, tigecycline nonsusceptibility is mediated by the AcrAB-TolC efflux pump, among others, and pump activity is often a downstream effect of mutations in their transcriptional regulators, cognate repressor genes, or noncoding regions, as demonstrated inEnterobacteriaceaeandAcinetobacterisolates. Here, we report the emergence of tigecycline nonsusceptibility in a longitudinal series of multidrug-resistant (MDR) and extensively drug-resistant (XDR)Klebsiella pneumoniaeisolates collected during tigecycline therapy and the elucidation of its resistance mechanisms. Clinical isolates were recovered prior to and during tigecycline therapy of a 2.5-month-old Honduran neonate. Antimicrobial susceptibility tests to tigecycline determined that the MIC increased from 1 to 4 μg/ml prior to the completion of tigecycline therapy. Unlike other studies, we did not find increased expression oframA,ramR,oqxA,acrB,marA, orrarAgenes by reverse transcription-quantitative PCR (qRT-PCR). Whole-genome sequencing revealed an IS5insertion element in nonsusceptible isolates 85 bp upstream of a putative efflux pump operon, here namedkpgABC, previously unknown to be involved in resistance. Introduction of thekpgABCgenes in a non-kpgABCbackground increased the MIC of tigecycline 4-fold and is independent of a functional AcrAB-TolC pump. This is the first report to propose a function forkpgABCand identify an insertion element whose presence correlated with thein vivodevelopment of tigecycline nonsusceptibility inK. pneumoniae.

scholarly journals Review of Ceftazidime-Avibactam for the Treatment of Infections Caused by Pseudomonas aeruginosa

Antibiotics ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1126
Author(s):  
George L. Daikos ◽  
Clóvis Arns da da Cunha ◽  
Gian Maria Rossolini ◽  
Gregory G. Stone ◽  
Nathalie Baillon-Plot ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Real World Data ◽  
Serious Infections ◽  
Tract Infections ◽  
Abdominal Infections ◽  
Hospital Acquired

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes a range of serious infections that are often challenging to treat, as this pathogen can express multiple resistance mechanisms, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes. Ceftazidime–avibactam is a combination antimicrobial agent comprising ceftazidime, a third-generation semisynthetic cephalosporin, and avibactam, a novel non-β-lactam β-lactamase inhibitor. This review explores the potential role of ceftazidime–avibactam for the treatment of P. aeruginosa infections. Ceftazidime–avibactam has good in vitro activity against P. aeruginosa relative to comparator β-lactam agents and fluoroquinolones, comparable to amikacin and ceftolozane–tazobactam. In Phase 3 clinical trials, ceftazidime–avibactam has generally demonstrated similar clinical and microbiological outcomes to comparators in patients with complicated intra-abdominal infections, complicated urinary tract infections or hospital-acquired/ventilator-associated pneumonia caused by P. aeruginosa. Although real-world data are limited, favourable outcomes with ceftazidime–avibactam treatment have been reported in some patients with MDR and XDR P. aeruginosa infections. Thus, ceftazidime–avibactam may have a potentially important role in the management of serious and complicated P. aeruginosa infections, including those caused by MDR and XDR strains.

scholarly journals In Vitro Activity of Cefiderocol Against a Broad Range of Clinically Important Gram-negative Bacteria

2019 ◽  
Vol 69 (Supplement_7) ◽  
pp. S544-S551 ◽  
Author(s):  
Yoshinori Yamano
Keyword(s):  
Efflux Pump ◽  
Bloodstream Infections ◽  
Resistance Mechanisms ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Highly Active ◽  
Carbapenem Resistant ◽  
Surveillance Programs ◽  
Tract Infections

AbstractCarbapenem-resistant gram-negative bacteria including Enterobacteriaceae as well as nonfermenters, such as Pseudomonas aeruginosa and Acinetobacter baumannii, have emerged as significant global clinical threats. Although new agents have recently been approved, none are active across the entire range of resistance mechanisms presented by carbapenem-resistant gram-negative bacteria. Cefiderocol, a novel siderophore cephalosporin, has been shown in large surveillance programs and independent in vitro studies to be highly active against all key gram-negative causative pathogens isolated from patients with hospital-acquired or ventilator-associated pneumonia, bloodstream infections, or complicated urinary tract infections. The improved structure, the novel mode of entry into bacteria, and its stability against carbapenemases enables cefiderocol to exhibit high potency against isolates that produce carbapenemases of all classes or are resistant due to porin channel mutations and/or efflux pump overexpression. Resistance to cefiderocol is uncommon and appears to be multifactorial.

scholarly journals Antimicrobial Susceptibility and Characterization of Resistance Mechanisms of Corynebacterium urealyticum Clinical Isolates

Antibiotics ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 404
Author(s):  
Itziar Chapartegui-González ◽  
Marta Fernández-Martínez ◽  
Ana Rodríguez-Fernández ◽  
Danilo J. P. Rocha ◽  
Eric R. G. R. Aguiar ◽  
...  
Keyword(s):  
Antimicrobial Susceptibility ◽  
Antimicrobial Agents ◽  
Point Mutations ◽  
Tetracycline Resistance ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistance Rate ◽  
Clinical Isolates ◽  
Tract Infections ◽  
Corynebacterium Urealyticum

Corynebacterium urealyticum is a non-diphtherial urease-producing clinically relevant corynebacterial, most frequently involved in urinary tract infections. Most of the C. urealyticum clinical isolates are frequently resistant to several antibiotics. We investigated the susceptibility of 40 C. urealyticum isolated in our institution during the period 2005–2017 to eight compounds representative of the main clinically relevant classes of antimicrobial agents. Antimicrobial susceptibility was determined by the Epsilometer test. Resistance genes were searched by PCR. All strains were susceptible to vancomycin whereas linezolid and rifampicin also showed good activity (MICs90 = 1 and 0.4 mg/L, respectively). Almost all isolates (39/40, 97.5%) were multidrug resistant. The highest resistance rate was observed for ampicillin (100%), followed by erythromycin (95%) and levofloxacin (95%). Ampicillin resistance was associated with the presence of the blaA gene, encoding a class A β-lactamase. The two rifampicin-resistant strains showed point mutations driving amino acid replacements in conserved residues of RNA polymerase subunit β (RpoB). Tetracycline resistance was due to an efflux-mediated mechanism. Thirty-nine PFGE patterns were identified among the 40 C. urealyticum, indicating that they were not clonally related, but producing sporadic infections. These findings raise the need of maintaining surveillance strategies among this multidrug resistant pathogen.

scholarly journals High Levels of Intrinsic Tetracycline Resistance inMycobacterium abscessusAre Conferred by a Tetracycline-Modifying Monooxygenase

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Paulami Rudra ◽  
Kelley Hurst-Hess ◽  
Pascal Lappierre ◽  
Pallavi Ghosh
Keyword(s):  
Bacterial Infections ◽  
Efflux Pump ◽  
Tetracycline Resistance ◽  
Resistance Mechanisms ◽  
Mycobacterium Abscessus ◽  
Repeat Sequence ◽  
Content Type ◽  
High Level

ABSTRACTTetracyclines have been one of the most successful classes of antibiotics. However, its extensive use has led to the emergence of widespread drug resistance, resulting in discontinuation of use against several bacterial infections. Prominent resistance mechanisms include drug efflux and the use of ribosome protection proteins. Infrequently, tetracyclines can be inactivated by the TetX class of enzymes, also referred to as tetracycline destructases. Low levels of tolerance to tetracycline inMycobacterium smegmatisandMycobacterium tuberculosishave been previously attributed to the WhiB7-dependent TetV/Tap efflux pump. However,Mycobacterium abscessusis ∼500-fold more resistant to tetracycline thanM. smegmatisandM. tuberculosis. In this report, we show that this high level of resistance to tetracycline and doxycycline inM. abscessusis conferred by a WhiB7-independent tetracycline-inactivating monooxygenase, MabTetX (MAB_1496c). The presence of sublethal doses of tetracycline and doxycycline results in a >200-fold induction of MabTetX, and an isogenic deletion strain is highly sensitive to both antibiotics. Further, purified MabTetX can rapidly monooxygenate both antibiotics. We also demonstrate that expression of MabTetX is repressed by MabTetRx, by binding to an inverted repeat sequence upstream of MabTetRx; the presence of either antibiotic relieves this repression. Moreover, anhydrotetracycline (ATc) can effectively inhibit MabTetX activityin vitroand decreases the MICs of both tetracycline and doxycyclinein vivo. Finally, we show that tigecycline, a glycylcycline tetracycline, not only is a poor substrate of MabTetX but also is incapable of inducing the expression of MabTetX. This is therefore the first demonstration of a tetracycline-inactivating enzyme in mycobacteria. It (i) elucidates the mechanism of tetracycline resistance inM. abscessus, (ii) demonstrates the use of an inhibitor that can potentially reclaim the use of tetracycline and doxycycline, and (iii) identifies two sequential bottlenecks—MabTetX and MabTetRx—for acquiring resistance to tigecycline, thereby reiterating its use againstM. abscessus.

scholarly journals Synergistic Effect of Propolis and Antibiotics on Uropathogenic Escherichia coli

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 739
Author(s):  
Jean-Philippe Lavigne ◽  
Jérémy Ranfaing ◽  
Catherine Dunyach-Rémy ◽  
Albert Sotto
Keyword(s):  
Escherichia Coli ◽  
Bacterial Infections ◽  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Uropathogenic Escherichia Coli ◽  
Resistant Bacteria ◽  
Minimal Inhibitory Concentrations ◽  
Tract Infections

Urinary tract infections (UTIs) are the most common bacterial infections around the world. Uropathogenic Escherichia coli (UPEC) is among the main pathogens isolated in UTIs. The rate of UPEC with high resistance towards antibiotics and multidrug-resistant bacteria have increased dramatically and conduct to the difficulty to treat UTIs. Due to the rarefaction of new antibiotics molecules, new alternative strategies must be evaluated. Since many years, propolis has demonstrated an interesting antibacterial activity against E. coli. Here, we evaluated its activity added to antibiotics on a panel of UPEC with different resistance mechanisms. Minimal inhibitory concentrations (MICs) and time–kill curves of fosfomycin, ceftriaxone, ertapenem and ofloxacin, with and without propolis, were determined. Significant diminution of the MICs was observed using ceftriaxone or ofloxacin + propolis. Propolis alone had a bacteriostatic activity with time-dependent effect against UPEC. The addition of this nutraceutical improved the effect of all the antibiotics evaluated (except fosfomycin) and showed a synergistic bactericidal effect (fractional inhibitory concentrations index ≤ 0.5 and a decrease ≥ 2 log CFU/mL for the combination of propolis plus antibiotics compared with the antibiotic alone). Propolis is able to restore in vitro antibiotic susceptibility when added to antibiotics against UPEC. This study showed that propolis could enhance the efficiency of antibiotics used in UTIs and could represent an alternative solution.

scholarly journals The Characteristic of Virulence, Biofilm and Antibiotic Resistance of Klebsiella pneumoniae

2020 ◽  
Vol 17 (17) ◽  
pp. 6278
Author(s):  
Guoying Wang ◽  
Guo Zhao ◽  
Xiaoyu Chao ◽  
Longxiang Xie ◽  
Hongju Wang
Keyword(s):  
Antibiotic Resistance ◽  
Klebsiella Pneumoniae ◽  
Resistance Mechanism ◽  
Current Medical Research ◽  
Opportunistic Pathogen ◽  
Multidrug Resistant ◽  
Current Medical ◽  
Tolerance Mechanisms ◽  
Rapid Spread ◽  
Tract Infections

Klebsiella pneumoniae is an important gram-negative opportunistic pathogen that causes a variety of infectious diseases, including urinary tract infections, bacteremia, pneumonia, and liver abscesses. With the emergence of multidrug-resistant (MDR) and hypervirulent K. pneumoniae (hvKP) strains, the rapid spread of these clinical strains in geography is particularly worrying. However, the detailed mechanisms of virulence and antibiotic resistance in K. pneumoniae are still not very clear. Therefore, studying and elucidating the pathogenic mechanisms and drug resistance mechanism of K. pneumoniae infection are important parts of current medical research. In this paper, we systematically summarized the virulence, biofilm, and antibiotic tolerance mechanisms of K. pneumoniae, and explored the application of whole genome sequencing and global proteomics, which will provide new clues for clinical treatment of K. pneumoniae.

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