scholarly journals Amino Acid Biosynthetic Pathways Are Required forKlebsiella pneumoniaeGrowth in Immunocompromised Lungs and Are Druggable Targets during Infection

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Rebecca J. Silver ◽  
Michelle K. Paczosa ◽  
Anne L. McCabe ◽  
Joan-Miquel Balada-Llasat ◽  
James D. Baleja ◽  
...  
Keyword(s):  
Amino Acid ◽  
Competitive Inhibitor ◽  
Multidrug Resistant ◽  
Biosynthetic Pathways ◽  
Epsp Synthase ◽  
Content Type ◽  
Resistant Strains ◽  
Resistant Mutants ◽  
Druggable Targets

ABSTRACTThe emergence of multidrug-resistantKlebsiella pneumoniaehas rendered a large array of infections difficult to treat. In a high-throughput genetic screen of factors required forK. pneumoniaesurvival in the lung, amino acid biosynthesis genes were critical for infection in both immunosuppressed and wild-type (WT) mice. The limited pool of amino acids in the lung did not change during infection and was insufficient forK. pneumoniaeto overcome attenuating mutations inaroA,hisA,leuA,leuB,serA,serB,trpE, andtyrAin WT and immunosuppressed mice. Deletion ofaroA, which encodes 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase class I, resulted in the most severe attenuation. Treatment with the EPSP synthase-specific competitive inhibitor glyphosate decreasedK. pneumoniaegrowth in the lungs.K. pneumoniaeexpressing two previously identified glyphosate-resistant mutations in EPSP synthase had significant colonization defects in lung infection. Selection and characterization of six spontaneously glyphosate-resistant mutants inK. pneumoniaeyielded no mutations inaroA. Strikingly, glyphosate treatment of mice lowered the bacterial burden of two of three spontaneous glyphosate-resistant mutants and further lowered the burden of the less-attenuated EPSP synthase catalytic mutant. Of 39 clinical isolate strains, 9 were resistant to glyphosate at levels comparable to those of selected resistant strains, and none appeared to be more highly resistant. These findings demonstrate amino acid biosynthetic pathways essential forK. pneumoniaeinfection are promising novel therapeutic targets.

scholarly journals Genome Dynamics of Vibrio cholerae Isolates Linked to Seasonal Outbreaks of Cholera in Dhaka, Bangladesh

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ramani Baddam ◽  
Nishat Sarker ◽  
Dilruba Ahmed ◽  
Razib Mazumder ◽  
Ahmed Abdullah ◽  
...  
Keyword(s):  
Vibrio Cholerae ◽  
Clonal Expansion ◽  
Multidrug Resistant ◽  
Whole Genome ◽  
Content Type ◽  
Selective Forces ◽  
Genomic Characterization ◽  
Resistant Strains ◽  
Genomic Data Analysis

ABSTRACT The temporal switching of serotypes from serotype Ogawa to Inaba and back to Ogawa was identified in Vibrio cholerae O1, which was responsible for seasonal outbreaks of cholera in Dhaka during the period 2015 to 2018. In order to delineate the factors responsible for this serotype transition, we performed whole-genome sequencing (WGS) of V. cholerae O1 multidrug-resistant strains belonging to both the serotypes that were isolated during this interval where the emergence and subsequent reduction of the Inaba serotype occurred. The whole-genome-based phylogenetic analysis revealed clonal expansion of the Inaba isolates mainly responsible for the peaks of infection during 2016 to 2017 and that they might have evolved from the prevailing Ogawa strains in 2015 which coclustered with them. Furthermore, the wbeT gene in these Inaba serotype isolates was inactivated due to insertion of a transposable element at the same position signifying the clonal expansion. Also, V. cholerae isolates in the Inaba serotype dominant clade mainly contained classical ctxB allele and revealed differences in the genetic composition of Vibrio seventh pandemic island II (VSP-II) and the SXT integrative and conjugative element (SXT-ICE) compared to those of Ogawa serotype strains which remerged in 2018. The variable presence of phage-inducible chromosomal island-like element 1 (PLE1) was also noted in the isolates of the Inaba serotype dominant clade. The detailed genomic characterization of the sequenced isolates has shed light on the forces which could be responsible for the periodic changes in serotypes of V. cholerae and has also highlighted the need to analyze the mobilome in greater detail to obtain insights into the mechanisms behind serotype switching. IMPORTANCE The switching of serotype from Ogawa to Inaba and back to Ogawa has been observed temporally in Vibrio cholerae O1, which is responsible for endemic cholera in Bangladesh. The serospecificity is key for effective intervention and for preventing cholera, a deadly disease that continues to cause significant morbidity and mortality worldwide. In the present study, WGS of V. cholerae allowed us to better understand the factors associated with the serotype switching events observed during 2015 to 2018. Genomic data analysis of strains isolated during this interval highlighted variations in the genes ctxB, tcpA, and rtxA and also identified significant differences in the genetic content of the mobilome, which included key elements such as SXT ICE, VSP-II, and PLE. Our results indicate that selective forces such as antibiotic resistance and phage resistance might contribute to the clonal expansion and predominance of a particular V. cholerae serotype responsible for an outbreak.

Characterization of swine isolates of Clostridium difficile in Spain: A potential source of epidemic multidrug resistant strains?

Anaerobe ◽  
2013 ◽  
Vol 22 ◽  
pp. 45-49 ◽  
Author(s):  
Teresa Peláez ◽  
Luis Alcalá ◽  
José L. Blanco ◽  
Sergio Álvarez-Pérez ◽  
Mercedes Marín ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Multidrug Resistant ◽  
Potential Source ◽  
Resistant Strains

Molecular and Epidemiological Characterization of Enterobacterial Multidrug-Resistant Strains in Tlemcen Hospital (Algeria) (2008–2010)

2013 ◽  
Vol 19 (3) ◽  
pp. 185-190 ◽  
Author(s):  
Zaket Baba Ahmed-Kazi Tani ◽  
Dominique Decré ◽  
Nathalie Genel ◽  
Zahia Boucherit-Otmani ◽  
Guillaume Arlet ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Resistant Strains ◽  
Epidemiological Characterization

scholarly journals Macrolides and β-Lactam Antibiotics Enhance C3b Deposition on the Surface of Multidrug-Resistant Streptococcus pneumoniae Strains by a LytA Autolysin-Dependent Mechanism

2012 ◽  
Vol 56 (11) ◽  
pp. 5534-5540 ◽  
Author(s):  
Elisa Ramos-Sevillano ◽  
Cinthya Rodríguez-Sosa ◽  
Roberto Díez-Martínez ◽  
María-José Giménez ◽  
Eduardo Olmedillas ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Multidrug Resistant ◽  
Therapeutic Strategies ◽  
Host Immune System ◽  
Content Type ◽  
Main Cell ◽  
Resistant Strains ◽  
Novel Therapeutic Strategies ◽  
Study Offer ◽  
Dependent Mechanism

ABSTRACTThe emergence ofStreptococcus pneumoniaestrains displaying high levels of multidrug resistance is of great concern worldwide and a serious threat for the outcome of the infection. Modifications of the bacterial envelope by antibiotics may assist the recognition and clearance of the pathogen by the host immune system. Recognition ofS. pneumoniaeresistant strains by the complement component C3b was increased in the presence of specific anti-pneumococcal antibodies and subinhibitory concentrations of different macrolides and β-lactam antibiotics for all the strains investigated. However, C3b levels were unchanged in the presence of serum containing specific antibodies and sub-MICs of levofloxacin. To investigate whether LytA, the main cell wall hydrolase ofS. pneumoniae, might be involved in this process,lytA-deficient mutants were constructed. In the presence of antibiotics, loss of LytA was not associated with enhanced C3b deposition on the pneumococcal surface, which confirms the importance of LytA in this interaction. The results of this study offer new insights into the development of novel therapeutic strategies using certain antibiotics by increasing the efficacy of the host immune response to efficiently recognize pneumococcal resistant strains.

scholarly journals In Vitro Antifungal Combination of Flucytosine with Amphotericin B, Voriconazole, or Micafungin against Candida auris Shows No Antagonism

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
A. L. Bidaud ◽  
F. Botterel ◽  
A. Chowdhary ◽  
E. Dannaoui
Keyword(s):  
Amphotericin B ◽  
Inhibitory Concentration ◽  
Geometric Mean ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Resistant Mutants ◽  
Hospital Acquired

ABSTRACT Candida auris is an emerging, multidrug-resistant pathogen responsible for invasive hospital-acquired infections. Flucytosine is an effective anti-Candida species drug, but which cannot be used as a monotherapy because of the risk of development of resistant mutants during treatment. It is, therefore, noteworthy to test possible combinations with flucytosine that may have a synergistic interaction. In this study, we determined the in vitro interaction between flucytosine and amphotericin B, micafungin, or voriconazole. These combinations have been tested against 15 C. auris isolates. The MIC ranges (geometric mean [Gmean]) of flucytosine, amphotericin B, micafungin, and voriconazole were 0.125 to 1 μg/ml (0.42 μg/ml), 0.25 to 1 μg/ml (0.66 μg/ml), 0.125 to 0.5 μg/ml (0.3 μg/ml), and 0.03 to 4 μg/ml (1.05 μg/ml), respectively. When tested in combination, indifferent interactions were mostly observed with fractional inhibitory concentration index values from 0.5 to 1, 0.31 to 1.01, and 0.5 to 1.06 for the combinations of flucytosine with amphotericin B, micafungin, and voriconazole, respectively. A synergy was observed for the strain CBS 10913 from Japan. No antagonism was observed for any combination. The combination of flucytosine with amphotericin B or micafungin may be relevant for the treatment of C. auris infections.

scholarly journals Streptococcus suis in Brazil: Genotypic, Virulence, and Resistance Profiling of Strains Isolated from Pigs between 2001 and 2016

Pathogens ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 31 ◽  
Author(s):  
Carlos E. C. Matajira ◽  
Luisa Z. Moreno ◽  
Andre P. Poor ◽  
Vasco T. M. Gomes ◽  
Andressa C. Dalmutt ◽  
...  
Keyword(s):  
Streptococcus Suis ◽  
Multidrug Resistant ◽  
Swine Industry ◽  
Pfge Typing ◽  
Resistance Selection ◽  
Important Challenge ◽  
Resistant Strains ◽  
Resistance Rates ◽  
Isolation Period

Streptococcus suis remains an important challenge for the worldwide swine industry. Considering that Brazil is a major pork producer and exporter, proper monitoring of the pathogen and resistance rates are required. We present here the characterization of Brazilian S. suis strains isolated over a 15 year period by pulsed-field gel electrophoresis (PFGE) typing, capsular, virulence, and antimicrobial resistance profiling. Serotype prevalence revealed a predominance of serotype 2/½ followed by 3, 7, 1/14, 6, 8, 18, 28, and 27; the latter had not yet been reported in Brazil. Resistance profiling enabled the differentiation of nine profiles presenting resistance to three and up to eight antimicrobial classes. Even though an association between the most resistant strains and isolation year starting from 2009 was observed, a high frequency of multidrug-resistant strains isolated from 2001 to 2003 was also detected. This suggests that despite the isolation period, S. suis strains already presented high resistance selection pressure. A slight association of serotype 2/½ with some virulence profiles and PFGE pulsotypes was also identified. Nevertheless, no clonal dispersion or persistency of clones over the analyzed years and herds was detected.

scholarly journals Lead Optimization of Dehydroemetine for Repositioned Use in Malaria

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Priyanka Panwar ◽  
Kepa K. Burusco ◽  
Muna Abubaker ◽  
Holly Matthews ◽  
Andrey Gutnov ◽  
...  
Keyword(s):  
De Novo ◽  
Antimalarial Activity ◽  
Drug Repositioning ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Synthetic Analogue ◽  
80S Ribosome ◽  
Content Type ◽  
Resistant Strains

ABSTRACT Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC50], 47 nM ± 2.1 nM [mean ± standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have less-cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modeled on the published emetine binding site on the cryo-electron microscopy (cryo-EM) structure with PDB code 3J7A (P. falciparum 80S ribosome in complex with emetine), and it was found that (−)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than did (−)-S,S-dehydroisoemetine. (−)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of P. falciparum compared with (−)-S,S-dehydroisoemetine (IC50, 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compound exhibited gametocidal properties with no cross-resistance against any of the multidrug-resistant strains tested. Drug interaction studies showed (−)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (−)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity affecting the mitochondrial membrane potential, indicating a possible multimodal mechanism of action.

scholarly journals Characterization of RelA in Acinetobacter baumannii

2020 ◽  
Vol 202 (12) ◽  
Author(s):  
María Pérez-Varela ◽  
Aimee R. P. Tierney ◽  
Ju-Sim Kim ◽  
Andrés Vázquez-Torres ◽  
Philip Rather
Keyword(s):  
Acinetobacter Baumannii ◽  
Galleria Mellonella ◽  
Multidrug Resistant ◽  
Cell Physiology ◽  
Content Type ◽  
Content Model ◽  
Transposon Insertion ◽  
Downstream Effectors

ABSTRACT In response to nutrient depletion, the RelA and SpoT proteins generate the signaling molecule (p)ppGpp, which then controls a number of downstream effectors to modulate cell physiology. In Acinetobacter baumannii strain AB5075, a relA ortholog (ABUW_3302) was identified by a transposon insertion that conferred an unusual colony phenotype. An in-frame deletion in relA (ΔrelA) failed to produce detectable levels of ppGpp when amino acid starvation was induced with serine hydroxamate. The ΔrelA mutant was blocked from switching from the virulent opaque colony variant (VIR-O) to the avirulent translucent colony variant (AV-T), but the rate of AV-T to VIR-O switching was unchanged. In addition, the ΔrelA mutation resulted in a pronounced hypermotile phenotype on 0.35% agar plates. This hypermotility was dependent on the activation of a LysR regulator ABUW_1132, which was required for expression of AbaR, a LuxR family quorum-sensing regulator. In the ΔrelA mutant, ABUW_1132 was also required for the increased expression of an operon composed of the ABUW_3766-ABUW_3773 genes required for production of the surfactant-like lipopeptide acinetin 505. Additional phenotypes identified in the ΔrelA mutant included (i) cell elongation at high density, (ii) reduced formation of persister cells tolerant to colistin and rifampin, and (iii) decreased virulence in a Galleria mellonella model. IMPORTANCE Acinetobacter baumannii is a pathogen of worldwide importance. Due to the increasing prevalence of antibiotic resistance, these infections are becoming increasingly difficult to treat. New therapies are required to combat multidrug-resistant isolates. The role of RelA in A. baumannii is largely unknown. This study demonstrates that like in other bacteria, RelA controls a variety of functions, including virulence. Strategies to inhibit the activity of RelA and the resulting production of ppGpp could inhibit virulence and may represent a new therapeutic approach.

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