Fast track — Research LettersLinezolid resistance in a clinical isolate of Staphylococcus aureus
Summary
The new oxazolidinone antimicrobial, linezolid, has been approved for the treatment of infections caused by various gram-positive bacteria, including meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Although instances of linezolid resistance in VRE have been reported, resistance has not been encountered among clinical isolates of S aureus. We have characterised an MRSA isolate resistant to linezolid that was recovered from a patient treated with this agent for dialysis-associated peritonitis.
References (5)
- RD Gonzales et al.
Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid
Lancer
(2001) - SM Swaney et al.
The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria
Antimicrob Agents Chemother
(1998)
Cited by (952)
Genetic variation in the BLM gene and its expression in the ovaries is closely related to kidding number in goats
2024, TheriogenologyBloom (BLM) helicase plays an important role in DNA replication and the maintenance of genome integrity. BLM protein deficiency, which plays a vital role in the sperm-egg union and germ-cell development during reproduction, can lead to severe DNA damage in goats. However, the effect of BLM protein deficiency on goat litter size has not been reported. Herein, we studied the association between the genetic variation in the BLM gene and the number of kids per litter in Guizhou white goats. We explored differences in the expression of the BLM protein in the follicles of single and multi-kid nanny goats. We also analyzed the effects of dysregulated BLM gene expression on the proliferation and apoptosis of ovarian granulosa cells and the expression of genes related to follicle development in goats. Five single nucleotide polymorphism (SNP) loci, including the non-synonymous mutations g.38179 A > G, g.40626 G > C and g.89621 T > G; the intron synonymous mutation g.56961 G > A and the exon synonymous mutation g.65796 C > T were found in the BLM gene. All SNPs loci were in Hardy-Weinberg equilibrium, and correlation analysis showed that the g.65796 C > T and g.89621 T > G loci polymorphism was strongly associated with litter size in the first three litters (P < 0.05). The diplogenotype Hap 2/2 (AAGGAACCTT) showed no significant difference in litter size between different births, indicating that the diploid genotype is stable in different litter sizes. Bioinformatics analysis showed that three non-synonymous mutation loci (p.T488A, p.A662S, and p.S1373A) could affect BLM protein stability, and mutations in p.T488A and p.S1373A led to changes in amino acid polarity and associated interactions. qPCR results showed that the expression level of the BLM gene in the uterus and ovaries of TT genotype nanny goats was significantly higher than that of GG genotype nanny goats. Indirect immunofluorescence assay (IF) showed that the BLM protein was significantly overexpressed in both the primordial and growing follicles of nanny goats with multiple kids (P < 0.01). Disrupting BLM gene expression in the ovarian granulosa cells down-regulated the expression of the Cyp19A1 gene. It also significantly inhibited the proliferation of follicles and induces early apoptosis of the granulosa cells. These findings confirm that polymorphism in the BLM gene is closely related to the littering traits of Guizhou white goats, and it affects the reproductive performance of nanny goats by regulating the development of the oocytes and granulosa cells. This work provides new evidence on the regulatory effect of the BLM gene on the litter size of nanny goats.
Chemical Approach for Investigation of the Structure-Activity Relationship of Salmycin and Identification of a Glycan-based Analogue for Drug Resistant Staphylococcus aureus
2024, Advanced Synthesis and CatalysisNew synthetic routes were devised for total synthesis of Fe3+‐bound (ferri−) salmycin B (Sal B) (1), glycan‐based Sal analogues 2–5 and their Fe3+‐unbound (desferri−) counterparts 1′–5′ for the structure to activity relationship (SAR) study. The results of SAR study reveal the effective structure of 1 and its desferri‐counterpart 1′ that are responsible for the observed inhibitory activity against Staphylococcus aureus (S. aureus). Among the analogues 2–5 and 2′–5′, glucose‐based analogue 2 and its desferri‐counterpart 2′ exhibited inhibitory potency comparable to 1 and 1′. Chemical modification of 2′ for further antibacterial study enabled us to discover desferri‐Sal analogue 7′ that endowed with a simpler pharmacophore structure but significantly higher antibacterial potency against methicillin‐sensitive and resistant S. aureus than the natural product 1′ and even the clinical vancomycin. Together with a better hydrolytic stability and shorter synthetic route, the analogue 7′ represents an attractive antibiotic lead for further exploration.
Rational utilization of 1,2,3-triazole scaffold in anti-MRSA drug development: Design strategies, structural insights and pharmacological outcomes
2024, Journal of Molecular StructureMethicillin-resistant Staphylococcus aureus (MRSA) is an important bacterial pathogen that has the capability to cause mild to life-threatening infections. It has posed a significant threat to the healthcare system across the globe since its emergence in the 1960s. Since then, it has rapidly evolved and developed resistance to various antibiotics from time to time and forced research groups to look for newer antibiotics. Currently, MRSA is resistant to the large portion of available antibiotics in clinical practice which created a global emergency to develop novel and effective antibiotics against MRSA. 1,2,3-Triazole is a diverse nucleus in the field of medicinal chemistry and bioisostere to amide, ester, carboxylic acid and other heterocyclic fragments as well as an integral part of antibacterial agents like cefatrizine and tazobactam, therefore act as an important tool for drug development targeting MRSA. This review will provide, (a) Key information about the pathogenesis and drug resistance pattern of MRSA among available antibiotics. (b) Rational design strategies utilized in the development of anti-MRSA agents using triazole nucleus and (c) Pharmacological outcomes along with a critical discussion on structure activity relationships. This review will help various research groups across the globe in designing novel, potent and effective anti-MRSA agents by rational utilization of 1,2,3-triazole nucleus to overcome drug resistance acquired by MRSA.
Structure-activity relationship (SAR) and antibacterial activity of pyrrolidine based hybrids: A review
2023, Journal of Molecular StructureBacterial infections are a major health problem globally with a continuous increase in death cases. The drug-resistance problem is associated with the available antibiotics making them ineffective against bacterial strains leading to more problems in curing bacterial infections. About 1.2 million deaths have been reported in 2019 as a consequence of infections caused by various antibiotic-resistant bacteria. Pyrrolidine compounds, a prominent family of synthetic and natural plant metabolites exhibit a wide range of pharmacological activities. Significant antibacterial activity has been demonstrated in a wide range of synthetic pyrrolidine derivatives with numerous derivatizations including quinoline, spiro, thiazole, thiourea and many other derivatives. In addition to being discovered as promising antibacterial drugs, pyrrolidine compounds have the fewest side effects. These compounds have demonstrated an extraordinary ability to modulate a wide range of targets to produce excellent in vitro antibacterial activity, primarily against Gram-positive and Gram-negative bacteria. The research examines the significance of pyrrolidine ring derivatives, the various substitution patterns on the ring site, stereo and specifically the structure-activity relationship (SAR) that influences the overall antibacterial activity of pyrrolidine-based hybrid compounds.
Increased copy number of 23S ribosomal RNA gene with point mutation in MRSA associated with linezolid resistance in a patient treated with long-term linezolid
2023, Journal of Infection and ChemotherapyMethicillin-resistant Staphylococcus aureus (MRSA) infection is one of the most difficult infections we have to treat. Linezolid is one of the effective treatment options for refractory MRSA infections. There are cases where we are forced to use long-term linezolid treatment for refractory MRSA infections.
To discuss the evolution of Linezolid resistance factors in clinical isolates of MRSA.
We investigated 16 MRSA isolated from a patient treated with linezolid for a long period of 75 days. We performed antibiotic susceptibility test, 23S rRNA genes sequencing analysis, Pulsed-field gel electrophoresis.
MRSA isolates were susceptible to linezolid before the start of treatment, but became less susceptible by prolonged treatment. The 23S rRNA sequencing analysis of linezolid-resistant strains that appeared 17 days after the start of treatment with linezolid revealed that all resistant MRSA had the G2576T substitution (Escherichia coli 23S rRNA gene number). The number of copies of this mutation increased with the use of linezolid.
Long-term use of linezolid in a patient or reuse of linezolid in a patient who has been previously treated with linezolid can lead to the emerging of linezolid-resistant MRSA in the host.
A novel nonsynonymous SNP in the OLR1 gene associated with litter size in Guizhou white goats
2023, TheriogenologyOxidized low-density lipoprotein receptor-1 (OLR1) encodes a low-density lipoprotein receptor belonging to the C-type lectin superfamily, which is closely related to reproduction. OLR1 is associated with fecundity in Awassi sheep. However, its effect on litter size has not been investigated in goats. In this study, OLR1 sequences and their mRNA expression levels in the gonadal axis of Guizhou white goats were evaluated to investigate the relationship between gene polymorphisms and litter size. In addition, the potential effects of a nonsynonymous substitution were evaluated using a bioinformatics approach. The expression levels of OLR1 were highest in the uterus of mothers with multiple kids and highest in the ovaries of mothers with single kids. OLR1 mRNA expression levels in the ovaries of mothers with single kids were two times higher than in the ovaries of mothers with multiple kids. The sequencing results revealed five SNPs in OLR1; however, only g.294 T > A, g.2260 T > C, and g.2268 C > T were significantly associated with litter size (P < 0.05). Linkage disequilibrium was detected between g.2260 T > C and g.2268 C > T (r2 = 0.322, D′ = 0.6). Additionally, goats with the Hap 1/1 diplotype had a greater litter size than others (P < 0.05). g.2260 T > C was a nonsynonymous mutation that resulted in the replacement of valine with alanine at the amino acid residue 54 of the OLR1 protein. Bioinformatic analyses revealed that the p.V54A locus was relatively conserved in cloven-hoofed species. Mutations at this locus could change the local conformation and reduce the stability of OLR1, affecting its half-life and the litter size of the nanny goat. These findings confirm that OLR1 affects goat kidding traits and provide a novel insight into the regulatory mechanism underlying the effect of OLR1 on litter size.