scholarly journals Generation and characterisation of P. falciparum parasites with a G358S mutation in the PfATP4 Na+ pump and clinically relevant levels of resistance to some PfATP4 inhibitors

2022 ◽  
Author(s):  
Deyun Qiu ◽  
Jinxin V. Pei ◽  
James E. O. Rosling ◽  
Dongdi Li ◽  
Yi Xue ◽  
...  
Keyword(s):  
Growth Rate ◽  
Clinical Trials ◽  
Inhibitory Concentration ◽  
Phase 1 ◽  
Clinical Development ◽  
Parasite Growth ◽  
Clinically Significant ◽  
Moderate Resistance ◽  
High Level ◽  
Level Resistance

Small-molecule inhibitors of PfATP4, a Plasmodium falciparum protein that is believed to pump Na+ out of the parasite while importing H+, are on track to become much-needed new antimalarial drugs. The spiroindolone cipargamin is poised to become the first PfATP4 inhibitor to reach the field, having performed strongly in Phase 1 and 2 clinical trials. Previous attempts to generate cipargamin-resistant parasites in the laboratory have yielded parasites with reduced susceptibility to the drug; however, the highest 50% inhibitory concentration reported to date is 24 nM. Here, we show that P. falciparum parasites can acquire a clinically-significant level of resistance to cipargamin that enables them to withstand micromolar concentrations of the drug. Independent experiments to generate high-level cipargamin resistance using different protocols and strains led to the same change each time - a G358S mutation in PfATP4. Parasites with this mutation showed high-level resistance not only to cipargamin, but also to the dihydroisoquinolone (+)-SJ733. However, for certain other (less clinically advanced) PfATP4-associated compounds the G358S mutation in PfATP4 conferred only moderate resistance or no resistance. The G358S mutation in PfATP4 did not affect parasite susceptibility to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation in the Toxoplasma gondii ATP4 homologue (G419S), decreased the sensitivity of the Na+-ATPase activity of ATP4 to inhibition by cipargamin and (+)-SJ733, and decreased the sensitivity of parasites expressing these ATP4 mutations to disruption of parasite Na+ regulation by cipargamin- and (+)-SJ733. The G358S mutation in PfATP4 reduced the affinity of the protein for Na+ and was associated with an increase in the parasite's resting cytosolic Na+ concentration; however, no significant defect in parasite growth rate was observed. Our findings suggest that codon 358 in pfatp4 should be monitored closely in the field as a molecular marker for cipargamin resistance, and that PfATP4 inhibitors in clinical development should be tested for their activity against PfATP4G358S parasites.

scholarly journals Hyper-Aerotolerant Campylobacter coli from Duck Sources and Its Potential Threat to Public Health: Virulence, Antimicrobial Resistance, and Genetic Relatedness

2019 ◽  
Vol 7 (11) ◽  
pp. 579 ◽  
Author(s):  
Jae-Ho Guk ◽  
Junhyung Kim ◽  
Hyokeun Song ◽  
Jinshil Kim ◽  
Jae-Uk An ◽  
...  
Keyword(s):  
Public Health ◽  
Antimicrobial Resistance ◽  
Inhibitory Concentration ◽  
Genetic Relatedness ◽  
Control Strategies ◽  
Campylobacter Coli ◽  
Potential Threat ◽  
High Level ◽  
Sequence Types ◽  
Level Resistance

Campylobacter, a common foodborne human pathogen, is considered sensitive to oxygen. Recently, aerotolerant (AT) Campylobacter jejuni with the ability to survive under aerobic stress has been reported. Here, we investigated the prevalence of hyper-aerotolerant (HAT) Campylobacter coli from duck sources (118 carcasses and meat) and its characteristics to assess potential impacts on public health. Half of 56 C. coli isolates were HAT and most harbored various virulence genes including flaA, cadF, cdtA, ceuB, and wlaN. Moreover, 98.2% of C. coli isolates showed resistance to quinolones, including ciprofloxacin (CIP), and nine (16.1%) showed high-level resistance to ciprofloxacin (Minimum Inhibitory Concentration, MIC ≥ 32 μg/mL) and most of these were HAT. Based on genetic relatedness between C. coli from duck sources and those from human sources (PubMLST and NCBI), HAT isolates sharing the same MLST sequence types were significantly more prevalent than those not sharing the same sequence types as those from human sources. Therefore, HAT C. coli is prevalent in duck sources, and is most likely transmitted to humans through the food chain given its aerotolerance. This being so, it might pose a threat to public health given its virulence and antimicrobial resistance (AMR). This study will assist in improving control strategies to reduce farm-to-table HAT C. coli transmission to humans.

scholarly journals Phenotypic characterization of R-factor tetracycline resistance determinants

1974 ◽  
Vol 24 (3) ◽  
pp. 333-343 ◽  
Author(s):  
T. J. Foster ◽  
Áine Walsh
Keyword(s):  
Tetracycline Resistance ◽  
Phenotypic Characterization ◽  
Resistance Determinants ◽  
R Factor ◽  
Moderate Resistance ◽  
High Level ◽  
R Factors ◽  
Phenotypic Groups ◽  
Level Resistance

SUMMARYThe tetracycline-resistance determinants of R-factors from different compatibility groups have been tested inEscherichia coliK12 and phenotypically classified into two major classes. Class I determinants confer high-level resistance to tetracycline (> 100 μg/ml) and moderate resistance to minocycline (5–25 μg/ml) while those of Class II gave moderate resistance to tetracycline (50–70 μg/ml) and low resistance to minocycline. Each class was subdivided because of variation in resistance profiles and in the abilities of tetracycline and minocycline to induce increased resistance. Strains carrying two compatible TetrR-factors of the same or different phenotypic groups did not show increased tetracycline resistance.

scholarly journals Human isolates of apramycin-resistant Escherichia coli which contain the genes for the AAC(3)IV enzyme

1993 ◽  
Vol 110 (2) ◽  
pp. 253-259 ◽  
Author(s):  
J. E. B. Hunter ◽  
C. A. Hart ◽  
J. C. Shelley ◽  
J. R. Walton ◽  
M. Bennett
Keyword(s):  
Escherichia Coli ◽  
Minimal Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Aminoglycoside Antibiotic ◽  
Dna Probe ◽  
Conjugative Plasmid ◽  
E Coli ◽  
High Level ◽  
Level Resistance

SUMMARYGentamicin-resistant Escherichia coli isolated at different periods from patients in two hospitals were tested for resistance to the aminoglycoside antibiotic apramycin. Twenty-four of 93 (26%) gentamicin-resistant isolates collected from the Royal Liverpool Hospital between 1981 and 1990 were resistant to apramycin. Thirteen isolates were highly resistant to apramycin (minimal inhibitory concentration (MIC) ≥ 1024 μg/ml). were also resistant to gentamicin, netilmicin and tobramycin, and hybridized with a DNA probe derived from the aminoglycoside acetyltransferase (3)IV (AAC(3)IV) gene. The proportion of gentamicinresistant isolates which had high level resistance to apramycin increased from 7% in 1981–5 to 24% in 1986–90.Twelve gentamicin-resistant E. coli from Guy's and St Thomas's Hospital isolated between 1977 and 1980 were also tested for resistance to apramycin. For five of these isolates the MICs of apramycin was 32–256 μg/ml. None was shown to have a conjugative plasmid carrying resistance to apramycin and only one hybridized with the DNA probe for the AAC(3)IV enzyme.

scholarly journals Evidence that there are two types of determinant for tetracycline resistance among R-factors

1978 ◽  
Vol 31 (1) ◽  
pp. 75-84 ◽  
Author(s):  
E. C. R. Reeve
Keyword(s):  
Growth Rate ◽  
Host Cell ◽  
Resistance Gene ◽  
Tetracycline Resistance ◽  
Repressor Gene ◽  
Homologous Group ◽  
R Factor ◽  
High Level ◽  
R Factors ◽  
Level Resistance

SUMMARYA series of derepressed mutants of the tetracycline resistance (T) determinant in R-factor R57 have been found to be repressor-negative and recessive to the T determinant in R6. It is shown that these (Tdr) mutants are dominant to the inducible T determinant in RPl, indicating that the T determinants in R57 and RP1 code for different repressors of the resistance gene. The same Tdr determinants are unstable in cells carrying both the R57 mutant and RP1, probably due to selection against the dominant Tdr gene because it depresses the growth rate of the host cell compared with its T+homologue. It is suggested that the T determinants giving high-level resistance in R57, R6 and R100 form one homologous group, probably disseminated by the transposon TnlO, while T determinants giving a much lower level of resistance, such as that in RP1, form a separate group, which may include those in R46, and R199. It is proposed that the gene responsible for tetracycline resistance should be designatedtetAand the repressor genetetI. The R57 Tdr mutants then have the genotypetetI−tetA+.

scholarly journals Global dissemination of tet(X3) and tet(X6) among livestock-associated Acinetobacter is sporadically mediated by highly diverse plasmidomes

2021 ◽  
Author(s):  
Kai Zhou ◽  
Yingying Cheng ◽  
Yang Liu ◽  
Yong Chen ◽  
Fuman Huang ◽  
...  
Keyword(s):  
Growth Rate ◽  
Phylogenetic Analysis ◽  
Environmental Samples ◽  
One Health ◽  
Clinical Effectiveness ◽  
Fold Increase ◽  
The Other ◽  
Swine Farm ◽  
High Level ◽  
Level Resistance

The emergence of plasmid-borne tet(X) genes mediates high-level resistance of tigecycline largely threatening its clinical effectiveness. Currently, the dissemination pattern of plasmid-borne tet(X) genes remains unclear. In this study, 684 fecal and environmental samples were collected at six livestock farms, and 15 tet(X)-positive Acinetobacter isolates were recovered, mainly including 9 tet(X3)- and 5 tet(X6)-positive A. towneri strains. A clonal dissemination of tet(X3)-positive A. towneri was detected in a swine farm, while the tet(X6)-positive A. towneri strains mainly sporadically disseminated in the same farm. A tet(X3)-carrying plasmid (pAT181) was self-transmissible from a tigecycline-susceptible A. towneri strain to A. baumannii ATCC17978, causing a 128-fold and 64-512-fold increase in the MIC values of tigecycline and the other tetracyclines, respectively. Worrisomely, pAT181 was stably maintained and increased the growth rate of ATCC17978. Further identification of tet(X)s in 10,680 Acinetobacter genomes retrieved from GenBank revealed that, tet(X3) (n=249) followed by tet(X5)-like (n=61) and tet(X6) (n=53) are the prevalent alleles mainly carried by four species, and most of them are livestock associated. Phylogenetic analysis showed that most of tet(X3) and tet(X6)-positive isolates disseminate sporadically. The structures of tet(X3) and tet(X6) plasmidomes are highly diverse and no epidemic plasmids have emerged yet. However, cross-species and cross-region transmissions of tet(X3) might have been mediated by several plasmids in a small proportion of strains. Our study evidence that tet(X3) and tet(X6) currently disseminate sporadically in Acinetobacter. Continuous surveillance for tet(X)s in the context of One Health is necessary to prevent them from transmitting to humans.

Penicillin- and Cephalosporin-Resistant Streptococcus pneumoniae: An Emerging Microbial Threat

PEDIATRICS ◽  
1994 ◽  
Vol 93 (3) ◽  
pp. 500-503 ◽  
Author(s):  
Robert J. Leggiadro
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pneumococcal Disease ◽  
Inhibitory Concentration ◽  
Penicillin Resistance ◽  
Cell Wall Synthesis ◽  
Penicillin Binding Proteins ◽  
Clinical Challenge ◽  
Recent Developments ◽  
High Level ◽  
Level Resistance

Recent reports from South Africa,1 Spain,2 Hungary,3 Texas,4-6 and Memphis7,8 document an increasing incidence of penicillin-resistant Streptococcus pneumoniae infections in children. The emergence of penicillin-resistant pneumococci that also demonstrate decreased susceptibility to extended-spectrum cephalosporins presents an even greater clinical challenge.6-9 This commentary reviews recent developments in the epidemiology, identification, and management of penicillin- and cephalosporin-resistant pneumococcal disease in children. Pneumococcal susceptibility to penicillin is defined as a minimal inhibitory concentration (MIC) <0.1 µg/mL. Intermediate (relative) penicillin resistance is defined as an MIC from 0.1 to 1.0 µg/mL and high-level resistance as an MIC >1.0 µ/mL. Pneumococcal penicillin resistance is mediated by alterations in penicillin-binding proteins involved in cell wall synthesis.10

scholarly journals High level resistance to Erythromycin and Tetracycline and dissemination of resistance determinants among clinical enterococci in Kerman-Iran

2021 ◽  
Author(s):  
Nikta Ahmadpoor ◽  
Roya Ahmadrajabi ◽  
Sarvenaz Esfahani ◽  
Zoya Hojabri ◽  
Mohammad Hassan Moshafi ◽  
...  
Keyword(s):  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Tetracycline Resistance ◽  
Resistance Mechanisms ◽  
Resistance Determinants ◽  
High Prevalence ◽  
Genes Encoding ◽  
High Level ◽  
O 31 ◽  
Level Resistance

Objectives: The purpose of this study was to investigate the distribution pattern of genes responsible for erythromycin and tetracycline resistance and their association with resistance phenotype in enterococci isolates. Materials and Methods: Eighty six Enterococcus faecalis and 26 E. faecium isolates were collected from two hospitals in Kerman-Iran. Minimum inhibitory concentration of erythromycin and tetracycline were determined and then, genes encoding resistance to erythromycin; erm (A-C), mef and msr -and tetracycline; tet (M), tet (O), tet (S), tet (K) and tet (L) – were investigated. Results: In all resistant isolates (n= 72, 64%), high level resistance to both tested antibiotics was found. The most prevalent erm gene was erm (B) (77.7%), followed by erm (A) (15.2%) and erm (C) (8.3%). Genes mediating erythromycin efflux, were detected in 70.8 % (mef) and 9.7% (msr) of resistant isolates. Regarding tetracycline, tet (M) was detected at the highest rate (50%), followed by tet (O) (31%) and tet (S) (11%). Export of tetracycline was found in 31% (tet (K)) and 12% (tet (L)) of isolates. Conclusion: High prevalence of high level resistance to both erythromycin and tetracycline was documented. The alteration at ribosomal level, had bigger role in erythromycin and tetracycline resistance than efflux systems. Concurrent resistance mechanisms were more involved in resistance to erythromycin than tetracycline.

scholarly journals 647. Investigation of Heteroresistance Among Klebsiella pneumoniae (KP) Inner Colonies (IC) Observed During Fosfomycin Disk Diffusion (DD) Testing

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S425-S426
Author(s):  
Morgan L Bixby ◽  
Amanda Krueger ◽  
Elizabeth B Hirsch
Keyword(s):  
Susceptibility Testing ◽  
Inhibitory Concentration ◽  
Small Subset ◽  
Zone Of Inhibition ◽  
Convenience Sample ◽  
European Committee ◽  
The One ◽  
High Level ◽  
Level Resistance ◽  
Mic Value

Abstract Background During fosfomycin DD testing, the frequent occurrence of non-susceptible IC within the zone of inhibition of susceptible isolates has been noted. The Clinical & Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) have contradicting recommendations on how IC should be interpreted; CLSI recommends considering IC when interpreting DD results whereas EUCAST recommends ignoring them. This study sought to identify the susceptibility of these IC and to understand whether heteroresistance contributes to the appearance of IC during fosfomycin DD. Methods This study included a convenience sample of 71 KP clinical isolates from 3 United States locations. During DD testing, 58 (81.7%) of these isolates displayed at least one IC. Broth microdilution (BMD) minimal inhibitory concentration (MIC) testing, using extrapolated CLSI Escherichia coli breakpoints, was performed on a subset (n=32) of the IC in duplicate for comparison to the corresponding parent MIC values. This was followed by a modified disk elution screening test for heteroresistance to compare the frequency of low level resistance (LLR) and high level resistance (HLR) between the susceptible isolates that produced resistant IC (n=6) and those that did not produce any IC (n=3). Results The MIC range for the IC isolates (128 to > 1024 μg/mL) increased as compared to the parent isolates (< 2 to > 256 μg/mL) and MIC50/90 increased from the parent (128/ > 256 μg/mL) to IC (1024/ > 1024 μg/mL) isolates. All IC isolates had a resistant MIC value vs. 46.5% of parent isolates, and over 90% of IC isolates had an MIC at least 2 dilutions higher than their corresponding parent isolate. Heteroresistance screening found all tested isolates to be positive for LLR, and 8 of 9 positive for HLR, while the one HLR-negative isolate was IC-producing. Conclusion IC were frequent during fosfomycin DD testing and were commonly more resistant than their corresponding KP parent isolates. A small subset of these isolates tested via a modified disk elution test displayed either LLR or HLR regardless of the absence of IC. These results call for further investigation among a larger isolate set to understand what mechanisms are responsible for the frequency of IC and their increased fosfomycin resistance. Disclosures All Authors: No reported disclosures

scholarly journals Anti-Mycoplasma Activity of Daptomycin and Its Use for Mycoplasma Elimination in Cell Cultures of Rickettsiae

Antibiotics ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 123 ◽  
Author(s):  
Wiwit Tantibhedhyangkul ◽  
Ekkarat Wongsawat ◽  
Sutthicha Matamnan ◽  
Naharuthai Inthasin ◽  
Jintapa Sueasuay ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Inhibitory Concentration ◽  
Mycoplasma Species ◽  
Intracellular Pathogens ◽  
Cellular Functions ◽  
Infected Cells ◽  
Mycoplasma Elimination ◽  
High Level ◽  
Level Resistance

Mycoplasma contamination detrimentally affects cellular functions and the growth of intracellular pathogens in cell cultures. Although several mycoplasmacidal agents are commercially available for sterile cell cultures, they are not applicable to rickettsia-infected cells. In our attempt to find an anti-mycoplasma drug for contaminated rickettsial cultures, we determined the susceptibilities of three common Mycoplasma species to daptomycin. Mycoplasma orale and M. arginini showed low-level resistance to daptomycin (minimum inhibitory concentration, MIC = 2 mg/L), whereas M. hyorhinis was high-level resistant (MIC = 32 mg/L). However, some Mycoplasma isolates developed higher resistance to daptomycin after failed treatments with inadequate doses or durations. An aminoglycoside (gentamicin) was still active against M. hyorhinis and could be used in Orientia cultures. For complete eradication of mycoplasmas in Rickettsia cultures, we recommend a 3-week treatment with daptomycin at 256 mg/L. In contaminated Orientia cultures, daptomycin at 32 mg/L was effective in eradicating M. orale, whereas either gentamicin or amikacin (100 mg/L) was effective in eradicating M. hyorhinis. Unlike each drug alone, the combinations of daptomycin plus clindamycin and/or quinupristin/dalfopristin proved effective in eradicating M. hyorhinis. In summary, our study demonstrated the in vitro anti-mycoplasma activity of daptomycin and its application as a new mycoplasma decontamination method for Rickettsia and Orientia cultures.

scholarly journals Characterization ofsal(A), a Novel Gene Responsible for Lincosamide and Streptogramin A Resistance in Staphylococcus sciuri

2014 ◽  
Vol 58 (6) ◽  
pp. 3335-3341 ◽  
Author(s):  
Chloé Hot ◽  
Nicolas Berthet ◽  
Olivier Chesneau
Keyword(s):  
Housekeeping Genes ◽  
Natural Resistance ◽  
Content Type ◽  
Expression Studies ◽  
Reverse Transcription Quantitative Pcr ◽  
Moderate Resistance ◽  
High Level ◽  
Reference Strains ◽  
Type Strains ◽  
Level Resistance

ABSTRACTNatural resistance to lincosamides and streptogramins A (LSA), which is a species characteristic ofBacillus subtilisandEnterococcus faecalis, has never been documented in theStaphylococcusgenus. We investigate here the molecular basis of the LSAphenotype exhibited by seven reference strains ofStaphylococcus sciuri, including the type strains of the three described subspecies. By whole-genome sequencing of strain ATCC 29059, we identified a candidate gene that encodes an ATP-binding cassette protein similar to the Lsa and VmlR resistance determinants. Isolation and reverse transcription-quantitative PCR (qRT-PCR) expression studies confirmed that Sal(A) can confer a moderate resistance to lincosamides (8 times the MIC of lincomycin) and a high-level resistance to streptogramins A (64 times the MIC of pristinamycin II). The chromosomal location ofsal(A) between two housekeeping genes of the staphylococcal core genome supports the gene's ancient origins and thus innate resistance to these antimicrobials withinS. sciurisubspecies.

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