scholarly journals Relationship between Glycopeptide Production and Resistance in the Actinomycete Nonomuraea sp. ATCC 39727

2014 ◽  
Vol 58 (9) ◽  
pp. 5191-5201 ◽  
Author(s):  
Giorgia Letizia Marcone ◽  
Elisa Binda ◽  
Lucia Carrano ◽  
Mervyn Bibb ◽  
Flavia Marinelli
Keyword(s):  
Antibiotic Resistance ◽  
Gene Dosage ◽  
Antibiotic Production ◽  
Resistance Mechanism ◽  
Biosynthetic Gene Cluster ◽  
Penicillin G ◽  
Glycopeptide Resistance ◽  
Content Type ◽  
High Level

ABSTRACTGlycopeptides and β-lactams inhibit bacterial peptidoglycan synthesis in Gram-positive bacteria; resistance to these antibiotics is studied intensively in enterococci and staphylococci because of their relevance to infectious disease. Much less is known about antibiotic resistance in glycopeptide-producing actinomycetes that are likely to represent the evolutionary source of resistance determinants found in bacterial pathogens.Nonomuraeasp. ATCC 39727, the producer of A40926 (the precursor for the semisynthetic dalbavancin), does not harbor the canonicalvanHAXgenes. Consequently, we investigated the role of the β-lactam-sensitived,d-peptidase/d,d-carboxypeptidase encoded byvanYn, the onlyvan-like gene found in the A40926 biosynthetic gene cluster, in conferring immunity to the antibiotic inNonomuraeasp. ATCC 39727. Taking advantage of the tools developed recently to genetically manipulate this uncommon actinomycete, we variedvanYngene dosage and expressedvanHatAatXatfrom the teicoplanin producerActinoplanes teichomyceticusinNonomuraeasp. ATCC 39727. Knocking outvanYn, complementing avanYnmutant, or duplicatingvanYnhad no effect on growth but influenced antibiotic resistance and, in the cases of complementation and duplication, antibiotic production.Nonomuraeasp. ATCC 39727 was found to be resistant to penicillins, but its glycopeptide resistance was diminished in the presence of penicillin G, which inhibits VanYnactivity. The heterologous expression ofvanHatAatXatincreased A40926 resistance inNonomuraeasp. ATCC 39727 but did not increase antibiotic production, indicating that the level of antibiotic production is not directly determined by the level of resistance. ThevanYn-based self-resistance inNonomuraeasp. ATCC 39727 resembles the glycopeptide resistance mechanism described recently in mutants ofEnterococcus faeciumselectedin vitrofor high-level resistance to glycopeptides and penicillins.

scholarly journals Self-Resistance and Cell Wall Composition in the Glycopeptide Producer Amycolatopsis balhimycina

2011 ◽  
Vol 55 (9) ◽  
pp. 4283-4289 ◽  
Author(s):  
Till F. Schäberle ◽  
Waldemar Vollmer ◽  
Hans-Jörg Frasch ◽  
Stephan Hüttel ◽  
Andreas Kulik ◽  
...  
Keyword(s):  
Cell Wall ◽  
Resistance Genes ◽  
Streptomyces Coelicolor ◽  
Resistance Mechanism ◽  
Biosynthetic Gene Cluster ◽  
Resistant Cell ◽  
Glycopeptide Resistance ◽  
Content Type ◽  
Constitutive Synthesis ◽  
Gene Orthologs

ABSTRACTThe prevailing resistance mechanism against glycopeptides in Gram-positive pathogens involves reprogramming the biosynthesis of peptidoglycan precursors, resulting ind-alanyl-d-lactate depsipeptide termini.Amycolatopsis balhimycinaproduces the vancomycin-like glycopeptide balhimycin and therefore has to protect itself from the action of the glycopeptide. We studied the roles of the accessory resistance gene orthologsvanYb,vnlRb, andvnlSb, which are part of the balhimycin biosynthetic gene cluster (represented by the subscript “b”). The VanYbcarboxypeptidase cleaved the terminald-Ala from peptidoglycan precursors, and its heterologous expression enhanced glycopeptide resistance inStreptomyces coelicolor. The VanRS-like two component system VnlRSbwas not involved in glycopeptide resistance or in the expression of thevanHAXglycopeptide resistance genes. MatureA. balhimycinapeptidoglycan contained mainly tri- and tetrapeptides, with only traces of thed-Ala-d-Ala-ending pentapeptides that are binding sites for the antibiotic produced. The structure of the peptidoglycan precursor is consistent with the presence ofvanHAXgenes, which were identified outside the balhimycin synthesis cluster. Both wild-type and non-antibiotic-producing mutant strains synthesized peptidoglycan precursors ending mainly withd-Lac, indicating constitutive synthesis of a resistant cell wall.A. balhimycinacould provide a model for an ancestral glycopeptide producer with constitutively expressed resistance genes.

scholarly journals Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01948-20
Author(s):  
Dalin Rifat ◽  
Si-Yang Li ◽  
Thomas Ioerger ◽  
Keshav Shah ◽  
Jean-Philippe Lanoix ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Evidence ◽  
Clinical Samples ◽  
Loss Of Function ◽  
Wild Type ◽  
Content Type ◽  
Solid Media ◽  
High Level ◽  
Level Resistance

ABSTRACTThe nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10−5 CFU. Whole-genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, of which 91% occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance, namely, fbiC (56%), fbiA (15%), ddn (12%), fgd (4%), and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983 (fbiD), a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples.

scholarly journals Infective Endocarditis Due to Corynebacterium Species: Clinical Features and Antibiotic Resistance

2021 ◽  
Vol 8 (3) ◽  
Author(s):  
Anna Bläckberg ◽  
Linn Falk ◽  
Karl Oldberg ◽  
Lars Olaison ◽  
Magnus Rasmussen
Keyword(s):  
Antibiotic Resistance ◽  
Infective Endocarditis ◽  
Prosthetic Valve Endocarditis ◽  
Penicillin G ◽  
Severe Condition ◽  
Ionization Time ◽  
Prosthetic Valves ◽  
Corynebacterium Species ◽  
Corynebacterium Striatum

Abstract Background Corynebacterium species are often dismissed as contaminants in blood cultures, but they can also cause infective endocarditis (IE), which is a severe condition. Antibiotic resistance of corynebacteria is increasing making treatment challenging. Reports on IE caused by Corynebacterium species are scarce and more knowledge is needed. Methods Cases of IE caused by Corynebacterium species were identified through the Swedish Registry of Infective Endocarditis. Isolates were collected for species redetermination by matrix-assisted laser desorption ionization-time of flight and for antibiotic susceptibility testing using Etests. Results Thirty episodes of IE due to Corynebacterium species were identified between 2008 and 2017. The median age of patients was 71 years (interquartile range, 60–76) and 77% were male. Corynebacterium striatum (n = 11) was the most common IE causing pathogen followed by Corynebacterium jeikeium (n = 5). Surgery was performed in 50% and in-hospital mortality rate was 13%. Patients with IE caused by Corynebacterium species were significantly more likely to have prosthetic valve endocarditis (70%), compared with patients with IE due to Staphylococcus aureus or non-beta-hemolytic streptococci (14% and 26%, respectively) (P < .0001). Vancomycin was active towards all Corynebacterium isolates, whereas resistance towards penicillin G was common. Conclusions Corynebacterium species cause IE, where prosthetic valves are mainly affected and surgery is often performed. Corynebacterium striatum is an important causative agent of IE within the genus. Antibiotic resistance of corynebacteria is relatively common but resistance towards vancomycin could not be detected in vitro.

scholarly journals Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates TargetingMycobacterium tuberculosisandMycobacterium abscessus

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Rashmi Gupta ◽  
Carolina Rodrigues Felix ◽  
Matthew P. Akerman ◽  
Kate J. Akerman ◽  
Cathryn A. Slabber ◽  
...  
Keyword(s):  
Mycobacterium Abscessus ◽  
Cross Resistance ◽  
Human Pathogens ◽  
Intrinsic Resistance ◽  
Content Type ◽  
Starting Point ◽  
Scalable Synthesis ◽  
High Level ◽  
Novel Drug

ABSTRACTMycobacterium tuberculosisand the fast-growing speciesMycobacterium abscessusare two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistantM. tuberculosisstrains and the high level of intrinsic resistance ofM. abscessuscall for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), againstM. abscessusandM. tuberculosis. We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicatingin vitroconditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverseM. tuberculosisandM. abscessusclinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target theM. tuberculosisgyrase.In vitroenzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity againstM. tuberculosisandM. abscessusthat act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.

scholarly journals Efficacy of Biocides Used in the Modern Food Industry To Control Salmonella enterica, and Links between Biocide Tolerance and Resistance to Clinically Relevant Antimicrobial Compounds

2012 ◽  
Vol 78 (9) ◽  
pp. 3087-3097 ◽  
Author(s):  
Orla Condell ◽  
Carol Iversen ◽  
Shane Cooney ◽  
Karen A. Power ◽  
Ciara Walsh ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Food Industry ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Antimicrobial Compounds ◽  
Cross Tolerance ◽  
Content Type ◽  
Food Grade ◽  
High Level

ABSTRACTBiocides play an essential role in limiting the spread of infectious disease. The food industry is dependent on these agents, and their increasing use is a matter for concern. Specifically, the emergence of bacteria demonstrating increased tolerance to biocides, coupled with the potential for the development of a phenotype of cross-resistance to clinically important antimicrobial compounds, needs to be assessed. In this study, we investigated the tolerance of a collection of susceptible and multidrug-resistant (MDR)Salmonella entericastrains to a panel of seven commercially available food-grade biocide formulations. We explored their abilities to adapt to these formulations and their active biocidal agents, i.e., triclosan, chlorhexidine, hydrogen peroxide, and benzalkonium chloride, after sequential rounds ofin vitroselection. Finally, cross-tolerance of different categories of biocidal formulations, their active agents, and the potential for coselection of resistance to clinically important antibiotics were investigated. Six of seven food-grade biocide formulations were bactericidal at their recommended working concentrations. All showed a reduced activity against both surface-dried and biofilm cultures. A stable phenotype of tolerance to biocide formulations could not be selected. Upon exposure ofSalmonellastrains to an active biocidal compound, a high-level of tolerance was selected for a number ofSalmonellaserotypes. No cross-tolerance to the different biocidal agents or food-grade biocide formulations was observed. Most tolerant isolates displayed changes in their patterns of susceptibility to antimicrobial compounds. Food industry biocides are effective against planktonicSalmonella. When exposed to sublethal concentrations of individual active biocidal agents, tolerant isolates may emerge. This emergence was associated with changes in antimicrobial susceptibilities.

scholarly journals Identification and Predictions Regarding the Biosynthesis Pathway of Polyene Macrolides Produced by Streptomyces roseoflavus Men-myco-93-63

2021 ◽  
Vol 87 (10) ◽  
Author(s):  
Xing Han ◽  
Jiao Wang ◽  
Lianna Liu ◽  
Fengying Shen ◽  
Qingfang Meng ◽  
...  
Keyword(s):  
Fermentation Broth ◽  
Pathogenic Fungi ◽  
Biosynthetic Gene Cluster ◽  
Inhibitory Effect ◽  
Plant Diseases ◽  
Active Metabolites ◽  
Content Type ◽  
Polyene Macrolides ◽  
Alternative Agent

ABSTRACT A group of polyene macrolides mainly composed of two constituents was isolated from the fermentation broth of Streptomyces roseoflavus Men-myco-93-63, which was isolated from soil where potato scabs were repressed naturally. One of these macrolides was roflamycoin, which was first reported in 1968, and the other was a novel compound named Men-myco-A, which had one methylene unit more than roflamycoin. Together, they were designated RM. This group of antibiotics exhibited broad-spectrum antifungal activities in vitro against 17 plant-pathogenic fungi, with 50% effective concentrations (EC50) of 2.05 to 7.09 μg/ml and 90% effective concentrations (EC90) of 4.32 to 54.45 μg/ml, which indicates their potential use in plant disease control. Furthermore, their biosynthetic gene cluster was identified, and the associated biosynthetic assembly line was proposed based on a module and domain analysis of polyketide synthases (PKSs), supported by findings from gene inactivation experiments. IMPORTANCE Streptomyces roseoflavus Men-myco-93-63 is a biocontrol strain that has been studied in our laboratory for many years and exhibits a good inhibitory effect in many crop diseases. Therefore, the identification of antimicrobial metabolites is necessary and our main objective. In this work, chemical, bioinformatic, and molecular biological methods were combined to identify the structures and biosynthesis of the active metabolites. This work provides a new alternative agent for the biological control of plant diseases and is helpful for improving both the properties and yield of the antibiotics via genetic engineering.

scholarly journals In Vitro Derivation of Fluoroquinolone-Resistant Mutants from Multiple Lineages of Haemophilus influenzae and Identification of Mutations Associated with Fluoroquinolone Resistance

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Hiroyuki Honda ◽  
Toyotaka Sato ◽  
Masaaki Shinagawa ◽  
Yukari Fukushima ◽  
Chie Nakajima ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Clinical Setting ◽  
Pathogenic Bacterium ◽  
Fluoroquinolone Resistance ◽  
Novel Mutations ◽  
Content Type ◽  
Resistant Mutants ◽  
High Level ◽  
Current Risk

ABSTRACT Haemophilus influenzae is a pathogenic bacterium that causes respiratory and otolaryngological infections. The increasing prevalence of β-lactamase–negative high-level ampicillin-resistant H. influenzae (high-BLNAR) is a clinical concern. Fluoroquinolones are alternative agents to β-lactams. However, the emergence and increasing prevalence of fluoroquinolone-resistant H. influenzae have been reported. The current risk of fluoroquinolone resistance in H. influenzae (especially in high-BLNAR) has not yet been evaluated. Here, we examined the development of fluoroquinolone resistance in fluoroquinolone-susceptible clinical H. influenzae isolates in vitro during passaging in the presence of moxifloxacin (from 0.03 to 128 mg/liter). Twenty-nine isolates were examined. Seventeen isolates (58.6%) showed reduced moxifloxacin susceptibility, and 10 of these 17 isolates (34.5% of all isolates) exceeded the Clinical and Laboratory Standards Institute breakpoint for moxifloxacin (MIC of >1 mg/liter) after repeat cultivation on moxifloxacin-containing agar. Seven of these ten isolates were high-BLNAR and represented multiple lineages. We identified 56 novel mutations in 45 genes induced during the development of fluoroquinolone resistance, except the defined quinolone resistance-determining regions (Ser84Leu and Asp88Tyr/Gly/Asn in GyrA and Gly82Asp, Ser84Arg, and Glu88Lys in ParC). Glu153Leu and ΔGlu606 in GyrA, Ser467Tyr and Glu469Asp in GyrB, and ompP2 mutations were novel mutations contributing to fluoroquinolone resistance in H. influenzae. In conclusion, H. influenzae clinical isolates from multiple lineages can acquire fluoroquinolone resistance by multiple novel mutations. The higher rate of derivation of fluoroquinolone-resistant H. influenzae from high-BLNAR than β-lactamase-negative ampicillin-susceptible isolates (P = 0.01) raises the possibility of the emergence and spread of fluoroquinolone-resistant high-BLNAR in the clinical setting.

scholarly journals Genomic and Functional Analysis of Emerging Virulent and Multidrug-Resistant Escherichia coli Lineage Sequence Type 648

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Katharina Schaufler ◽  
Torsten Semmler ◽  
Lothar H. Wieler ◽  
Darren J. Trott ◽  
Johann Pitout ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
High Risk ◽  
Multidrug Resistant ◽  
Phenotypic Analysis ◽  
Content Type ◽  
Extended Spectrum Beta Lactamase ◽  
Niche Adaptation ◽  
High Level

ABSTRACT The pathogenic extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli lineage ST648 is increasingly reported from multiple origins. Our study of a large and global ST648 collection from various hosts (87 whole-genome sequences) combining core and accessory genomics with functional analyses and in vivo experiments suggests that ST648 is a nascent and generalist lineage, lacking clear phylogeographic and host association signals. By including large numbers of ST131 (n = 107) and ST10 (n = 96) strains for comparative genomics and phenotypic analysis, we demonstrate that the combination of multidrug resistance and high-level virulence are the hallmarks of ST648, similar to international high-risk clonal lineage ST131. Specifically, our in silico, in vitro, and in vivo results demonstrate that ST648 is well equipped with biofilm-associated features, while ST131 shows sophisticated signatures indicative of adaption to urinary tract infection, potentially conveying individual ecological niche adaptation. In addition, we used a recently developed NFDS (negative frequency-dependent selection) population model suggesting that ST648 will increase significantly in frequency as a cause of bacteremia within the next few years. Also, ESBL plasmids impacting biofilm formation aided in shaping and maintaining ST648 strains to successfully emerge worldwide across different ecologies. Our study contributes to understanding what factors drive the evolution and spread of emerging international high-risk clonal lineages.

scholarly journals Contributions ofyap1Mutation and SubsequentatrFUpregulation to Voriconazole Resistance inAspergillus flavus

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Yuuta Ukai ◽  
Miho Kuroiwa ◽  
Naoko Kurihara ◽  
Hiroki Naruse ◽  
Tomoyuki Homma ◽  
...  
Keyword(s):  
Point Mutation ◽  
Nuclear Export ◽  
Resistance Mechanism ◽  
Resistant Mutant ◽  
Gene Replacement ◽  
Bzip Transcription Factor ◽  
Homologous Gene ◽  
Sequencing Analysis ◽  
Content Type

ABSTRACTAspergillus flavusis the second most significant pathogenic cause of invasive aspergillosis; however, its emergence risks and mechanisms of voriconazole (VRC) resistance have not yet been elucidated in detail. Here, we demonstrate that repeated exposure ofA. flavusto subinhibitory concentrations of VRCin vitrocauses the emergence of a VRC-resistant mutant with a novel resistance mechanism. The VRC-resistant mutant shows a MIC of 16 μg/ml for VRC and of 0.5 μg/ml for itraconazole (ITC). Whole-genome sequencing analysis showed that the mutant possesses a point mutation inyap1, which encodes a bZIP transcription factor working as the master regulator of the oxidative stress response, but no mutations in thecyp51genes. This point mutation inyap1caused alteration of Leu558 to Trp (Yap1Leu558Trp) in the putative nuclear export sequence in the carboxy-terminal cysteine-rich domain of Yap1. This Yap1Leu558Trpsubstitution was confirmed as being responsible for the VRC-resistant phenotype, but not for that of ITC, by the revertant to Yap1wild typewith homologous gene replacement. Furthermore, Yap1Leu558Trpcaused marked upregulation of theatrFATP-binding cassette transporter, and the deletion ofatrFrestored susceptibility to VRC inA. flavus. These findings provide new insights into VRC resistance mechanisms via a transcriptional factor mutation that is independent of thecyp51gene mutation inA. flavus.

scholarly journals Oritavancin Activity against Vancomycin-Susceptible and Vancomycin-Resistant Enterococci with Molecularly Characterized Glycopeptide Resistance Genes Recovered from Bacteremic Patients, 2009-2010

2011 ◽  
Vol 56 (3) ◽  
pp. 1639-1642 ◽  
Author(s):  
Rodrigo E. Mendes ◽  
Leah N. Woosley ◽  
David J. Farrell ◽  
Helio S. Sader ◽  
Ronald N. Jones
Keyword(s):  
Resistance Genes ◽  
Glycopeptide Resistance ◽  
Content Type ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant

ABSTRACTOritavancin exhibited potent activity against vancomycin-susceptible (MIC50and MIC90, 0.015/0.03 μg/ml) andvanB-carryingE. faecalisisolates (MIC50and MIC90, 0.015 and 0.015 μg/ml). Higher (16- to 32-fold) MIC50s and MIC90s forvanA-harboringE. faecaliswere noted (MIC50and MIC90, 0.25 and 0.5 μg/ml), although oritavancin inhibited all strains at ≤0.5 μg/ml. Vancomycin-susceptible andvanB-carryingE. faeciumstrains (MIC50and MIC90, ≤0.008 and ≤0.008 μg/ml for both) were very susceptible to oritavancin, as were VanA-producing isolates (MIC50and MIC90, 0.03 and 0.06 μg/ml). Oritavancin exhibited goodin vitropotency against this collection of organisms, including vancomycin-resistant enterococci.

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