scholarly journals Selection and characterisation of murine leukaemia L1210 cells with high-level resistance to the cytostatic activity of the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA)

1998 ◽  
Vol 1402 (1) ◽  
pp. 29-38 ◽  
Author(s):  
J Balzarini ◽  
S Hatse ◽  
L Naesens ◽  
E De Clercq
Keyword(s):  
Cytostatic Activity ◽  
L1210 Cells ◽  
Acyclic Nucleoside ◽  
High Level ◽  
Acyclic Nucleoside Phosphonate ◽  
Level Resistance

scholarly journals Antimalarial and toxic effects of the acyclic nucleoside phosphonate (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine in Plasmodium berghei-infected mice.

1996 ◽  
Vol 40 (7) ◽  
pp. 1584-1588 ◽  
Author(s):  
L J Smeijsters ◽  
H Nieuwenhuijs ◽  
R C Hermsen ◽  
G M Dorrestein ◽  
F F Franssen ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Intraperitoneal Administration ◽  
Repeated Administration ◽  
Toxicological Studies ◽  
Prophylactic Drug ◽  
Acyclic Nucleoside ◽  
High Doses ◽  
High Level ◽  
Acyclic Nucleoside Phosphonate

Plasmodium berghei-infected mice died with low levels of parasitemia after repeated intraperitoneal administration (five times at 15 mg kg of body weight-1 every other day) of the in vitro active antimalarial acyclic nucleoside phosphonate (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA]. Toxicological studies showed that the main cause of death resulted from (S)-HPMPA-induced nephrotoxicity. Although concomitant intraperitoneal administration of the tubular epithelium transport blocker probenecid prevented (S)-HPMPA-induced toxicity, mice eventually died with a high level of parasitemia, despite repeated administration of high doses of (S)-HPMPA. The short half-life of (S)-HPMPA in plasma combined with the insusceptibility of the nonreplicative stages of the parasite to (S)-HPMPA could explain this failure to eradicate all parasites. Indeed, a low but sustained (calculated) level of 200 nM (S)-HPMPA in plasma completely cured P. berghei-infected mice. However, these mice, which received a total dose of only 28 mg kg-1 administered via osmotic pumps for 7 days, died because of the toxicity of the drug. These findings indicate that nephrotoxicity hinders the use of (S)-HPMPA as a drug against blood stage parasites. An alternative application of (S)-HPMPA as a potent prophylactic drug is discussed.

The Chemistry of Drugs to Treat Candida albicans

2019 ◽  
Vol 19 (28) ◽  
pp. 2554-2566 ◽  
Author(s):  
Aurelio Ortiz ◽  
Estibaliz Sansinenea
Keyword(s):  
Candida Species ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Drug Classes ◽  
Life Threatening ◽  
Antifungal Substances ◽  
High Level ◽  
Systemic Infections ◽  
New Compounds ◽  
Level Resistance

Background:: Candida species are in various parts of the human body as commensals. However, they can cause local mucosal infections and, sometimes, systemic infections in which Candida species can spread to all major organs and colonize them. Objective:: For the effective treatment of the mucosal infections and systemic life-threatening fungal diseases, a considerably large number of antifungal drugs have been developed and used for clinical purposes that comprise agents from four main drug classes: the polyenes, azoles, echinocandins, and antimetabolites. Method: : The synthesis of some of these drugs is available, allowing synthetic modification of the molecules to improve the biological activity against Candida species. The synthetic methodology for each compound is reviewed. Results: : The use of these compounds has caused a high-level resistance against these drugs, and therefore, new antifungal substances have been described in the last years. The organic synthesis of the known and new compounds is reported. Conclusion: : This article summarizes the chemistry of the existing agents, both the old drugs and new drugs, in the treatment of infections due to C. albicans, including the synthesis of the existing drugs.

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 Molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae

2021 ◽  
Author(s):  
J G E Laumen ◽  
S S Manoharan-Basil ◽  
E Verhoeven ◽  
S Abdellati ◽  
I De Baetselier ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Ribosomal Proteins ◽  
Efflux Pump ◽  
23S Rrna ◽  
Rrna Gene ◽  
23S Rrna Gene ◽  
Evolution Of Resistance ◽  
High Level ◽  
Azithromycin Resistance ◽  
Level Resistance

Abstract Background The prevalence of azithromycin resistance in Neisseria gonorrhoeae is increasing in numerous populations worldwide. Objectives To characterize the genetic pathways leading to high-level azithromycin resistance. Methods A customized morbidostat was used to subject two N. gonorrhoeae reference strains (WHO-F and WHO-X) to dynamically sustained azithromycin pressure. We tracked stepwise evolution of resistance by whole genome sequencing. Results Within 26 days, all cultures evolved high-level azithromycin resistance. Typically, the first step towards resistance was found in transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34 respectively), followed by mutations in the MtrCDE-encoded efflux pump and the 23S rRNA gene. Low- to high-level resistance was associated with mutations in the ribosomal proteins and MtrCDE efflux pump. However, high-level resistance was consistently associated with mutations in the 23S ribosomal RNA, mainly the well-known A2059G and C2611T mutations, but also at position A2058G. Conclusions This study enabled us to track previously reported mutations and identify novel mutations in ribosomal proteins (L4, L22 and L34) that may play a role in the genesis of azithromycin resistance in N. gonorrhoeae.

scholarly journals WGS of Commensal Neisseria Reveals Acquisition of a New Ribosomal Protection Protein (MsrD) as a Possible Explanation for High Level Azithromycin Resistance in Belgium

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 384
Author(s):  
Tessa de Block ◽  
Jolein Gyonne Elise Laumen ◽  
Christophe Van Dijck ◽  
Said Abdellati ◽  
Irith De Baetselier ◽  
...  
Keyword(s):  
Integration Site ◽  
Bacterial Species ◽  
Resistance Mechanism ◽  
Health Concern ◽  
Sex With Men ◽  
High Level ◽  
Ribosomal Protection Protein ◽  
Commensal Neisseria ◽  
Level Resistance ◽  
Ribosomal Protection

In this study, we characterized all oropharyngeal and anorectal isolates of Neisseria spp. in a cohort of men who have sex with men. This resulted in a panel of pathogenic Neisseria (N. gonorrhoeae [n = 5] and N. meningitidis [n = 5]) and nonpathogenic Neisseria (N. subflava [n = 11], N. mucosa [n = 3] and N. oralis [n = 2]). A high proportion of strains in this panel were resistant to azithromycin (18/26) and ceftriaxone (3/26). Whole genome sequencing (WGS) of these strains identified numerous mutations that are known to confer reduced susceptibility to azithromycin and ceftriaxone in N. gonorrhoeae. The presence or absence of these known mutations did not explain the high level resistance to azithromycin (>256 mg/L) in the nonpathogenic isolates (8/16). After screening for antimicrobial resistance (AMR) genes, we found a ribosomal protection protein, Msr(D), in these highly azithromycin resistant nonpathogenic strains. The complete integration site originated from Streptococcus pneumoniae and is associated with high level resistance to azithromycin in many other bacterial species. This novel AMR resistance mechanism to azithromycin in nonpathogenic Neisseria could be a public health concern if it were to be transmitted to pathogenic Neisseria. This study demonstrates the utility of WGS-based surveillance of nonpathogenic Neisseria.

scholarly journals ArmA Methyltransferase in a Monophasic Salmonella enterica Isolate from Food

2011 ◽  
Vol 55 (11) ◽  
pp. 5262-5266 ◽  
Author(s):  
Sophie A. Granier ◽  
Laura Hidalgo ◽  
Alvaro San Millan ◽  
Jose Antonio Escudero ◽  
Belen Gutierrez ◽  
...  
Keyword(s):  
16S Rrna ◽  
Salmonella Enterica ◽  
Multidrug Resistant ◽  
Broad Host Range ◽  
En Bloc ◽  
Content Type ◽  
Route Of Transmission ◽  
Amoxicillin Clavulanate ◽  
High Level ◽  
Level Resistance

ABSTRACTThe 16S rRNA methyltransferase ArmA is a worldwide emerging determinant that confers high-level resistance to most clinically relevant aminoglycosides. We report here the identification and characterization of a multidrug-resistantSalmonella entericasubspecies I.4,12:i:− isolate recovered from chicken meat sampled in a supermarket on February 2009 in La Reunion, a French island in the Indian Ocean. Susceptibility testing showed an unusually high-level resistance to gentamicin, as well as to ampicillin, expanded-spectrum cephalosporins and amoxicillin-clavulanate. Molecular analysis of the 16S rRNA methyltransferases revealed presence of thearmAgene, together withblaTEM-1,blaCMY-2, andblaCTX-M-3. All of these genes could be transferreden blocthrough conjugation intoEscherichia coliat a frequency of 10−5CFU/donor. Replicon typing and S1 pulsed-field gel electrophoresis revealed that thearmAgene was borne on an ∼150-kb broad-host-range IncP plasmid, pB1010. To elucidate howarmAhad integrated in pB1010, a PCR mapping strategy was developed for Tn1548, the genetic platform forarmA.The gene was embedded in a Tn1548-like structure, albeit with a deletion of the macrolide resistance genes, and an IS26was inserted within themelgene. To our knowledge, this is the first report of ArmA methyltransferase in food, showing a novel route of transmission for this resistance determinant. Further surveillance in food-borne bacteria will be crucial to determine the role of food in the spread of 16S rRNA methyltransferase genes worldwide.

Sign in / Sign up

Export Citation Format

Share Document