Activity Of Linezolid Research Articles

Enhancing linezolid activity in the treatment of oral biofilms using novel chitosan microneedles with iontophoretic control

This study aimed to prepare and assess active microneedle (MN) patches based on a novel biomaterial and their effective coupled (physical and electrical) transdermal delivery of a model drug (Linezoid). Modified MN patches (e.g. fabricated from Linezoid, boronated chitosan, polyvinyl alcohol and D-sorbitol) were engineered using a vacuum micromoulding method. Physicochemical, FTIR (Fourier transform infrared), in-silico, structural and thermal analysis of prepared formulations were conducted to ascertain MN quality, composition and integrity. In-vitro mechanical tests, membrane toxicity, drug release, antibiofilm, ex-vivo mucoadhesion, insertion and in-vivo antibiofilm studies were performed to further validate viability of the coupled system. Optimized MN patch formulation (CSHP3 - comprising of 3 % w/v boronated chitosan, 3.5 % w/v PVA and 10 % w/w D-sorbitol) exhibited sharp-tipped, equi-distant and uniform-surfaced micron-scaled projections with conforming physicochemical features. FTIR analysis confirmed modification (i.e., boronation) of chitosan and compatibility as well as interaction between CSHP3 constituents. In-silico analysis indicated non-covalent interactions between all formulation constituents. Moreover, boronated chitosan-mucin glycoprotein complex showed a stronger bonding (∼1.86 times higher CScore) as compared to linezolid-mucin counterpart. Thermal analysis indicated amorphous nature of CSHP3. A ∼ 1.42 times higher tensile strength was displayed by CSHP3 as compared to control (i.e., pure chitosan, polyvinyl alcohol and D-sorbitol-based MN patch). Membrane toxicity study indicated non-toxic and physiological compatible nature of CSHP3. Within 90 min, 91.99 ± 2.3 % linezolid was released from CSHP3. During release study on agarose gel, CSHP3-iontophoresis treatment resulted in a ∼ 1.78 and ∼ 1.20 times higher methylene blue-covered area and optical density, respectively, within 60 min as compared to CSHP3 treatment alone. Staphylococcus aureus biofilms treated with CSHP3 exhibited 65 ± 4.2 % reduction in their mass. CSHP3 MN patches remained adhered to the rabbit oral mucosa for 6 ± 0.15 h. Mucosa treated with CSHP3 and CSHP3-iontophoresis combination showed a generation of pathways in the epithelium layers without any damage to the underlying lamina propria. Eradication of Staphylococcus aureus from oral mucosal wounds and complete tissue regeneration was recorded following 7-day treatment using CSHP3-iontophoresis coupled approach.

Synthesis, biological evaluation and molecular docking study of pyrimidine linked thiazolidinedione derivatives as potential antimicrobial and antitubercular agents

The design and development of novel antimicrobial agents are highly desired to combat the emergence of medication resistance against microorganisms that cause infections. A series of new pyrimidine-linked thiazolidinedione derivatives (5a-j) were synthesized, characterized, and their antimicrobial properties assessed in the current investigation. Here, novel pyrimidine-linked thiazolidinedione compounds were designed using the molecular hybridization approach. Elemental and spectral techniques were used to determine the structures of the synthesized hybrids. The majority of compounds showed encouraging antibacterial properties. Among the active compounds, 5g, 5i, and 5j showed 1.85, 1.15, and 1.38 times the activity of streptomycin against S. aureus, respectively, with MIC values of 6.4, 10.3, and 8.6 µM. With MIC values of 10.8, 21.9, and 15.4 µM, respectively, the compounds 5g, 5i, and 5j showed 2.14, 1.05, and 1.50 times the activity of linezolid against the methicillin-resistant S. aureus (MRSA) strain. Furthermore, when compared to the reference medications, compounds 5g, 5i, and 5j demonstrated broad-range antimicrobial efficacy against all tested strains of bacteria and fungus. Out of all the compounds that were investigated, compounds 5g, 5i, and 5j showed noteworthy anti-tubercular activity. 5g is the most effective, 1.59 times more effective than reference drug isoniazid. To anticipate the binding manner, the synthesized potent compounds were subjected to molecular docking into the active binding site of MRSA and the mycobacterial membrane protein large 3 (MmpL3) protein. The compounds 5g, 5i, and 5j may eventually serve as lead compounds in the search for antimicrobial and anti-TB therapeutic agents.

Antimicrobial Activity of Ceragenins against Vancomycin-Susceptible and -Resistant Enterococcus spp.

Ceragenins (CSAs) are a new class of antimicrobial agents designed to mimic the activities of endogenous antimicrobial peptides. In this study, the antibacterial activities of various ceragenins (CSA-13, CSA-44, CSA-90, CSA-131, CSA-138, CSA-142, and CSA-192), linezolid, and daptomycin were assessed against 50 non-repeated Enterococcus spp. (17 of them vancomycin-resistant Enterococcus-VRE) isolated from various clinical specimens. Among the ceragenins evaluated, the MIC50 and MIC90 values of CSA-44 and CSA-192 were the lowest (2 and 4 μg/mL, respectively), and further studies were continued with these two ceragenins. Potential interactions between CSA-44 or CSA-192 and linezolid were tested and synergistic interactions were seen with the CSA-192-linezolid combination against three Enterococcus spp., one of them VRE. The effects of CSA-44 and CSA-192 on the MIC values of vancomycin were also investigated, and the largest MIC change was seen in the vancomycin-CSA-192 combination. The in vivo effects of CSA-44 and CSA-192 were evaluated in a Caenorhabditis elegans model system. Compared to no treatment, increased survival was observed with C. elegans when treated with ceragenins. In conclusion, CSA-44 and CSA-192 appear to be good candidates (alone or in combination) for the treatment of enterococcal infections, including those from VRE.

The Synergistic Activity of Rhamnolipid Combined with Linezolid against Linezolid-Resistant Enterococcus faecium.

Enterococci resistance is increasing sharply, which poses a serious threat to public health. Rhamnolipids are a kind of amphiphilic compound used for its bioactivities, while the combination of nontraditional drugs to restore linezolid activity is an attractive strategy to treat infections caused by these pathogens. This study aimed to investigate the activity of linezolid in combination with the rhamnolipids against Enterococcus faecium. Here, we determined that the rhamnolipids could enhance the efficacy of linezolid against enterococci infections by a checkerboard MIC assay, a time-kill assay, a combined disk test, an anti-biofilm assay, molecular simulation dynamics, and mouse infection models. We identified that the combination of rhamnolipids and linezolid restored the linezolid sensitivity. Anti-biofilm experiments show that our new scheme can effectively inhibit biofilm generation. The mouse infection model demonstrated that the combination therapy significantly reduced the bacterial load in the feces, colons, and kidneys following subcutaneous administration. This study showed that rhamnolipids could play a synergistic role with linezolid against Enterococcus. Our combined agents could be appealing candidates for developing new combinatorial agents to restore antibiotic efficacy in the treatment of linezolid-resistant Enterococcus infections.

The Glycopeptide-Susceptibility of Multidrug-Resistant/Extensively Drug-Resistant Staphylococcus aureus in Skin Infections

Background: The prevalence of drug-resistant Staphylococcus aureus is increasing alarmingly, limiting treatment options. Objectives: This study was conducted to investigate the minimum inhibitory concentration (MIC) of glycopeptides against multidrug-resistant (MDR) and extensively drug-resistant (XDR) S. aureus isolates from patients with skin infections. Methods: In this study, S. aureus isolates were collected from outpatients with skin infections (n = 250) during 2019 - 2022. The isolates were identified using routine microbiological and biochemical tests. Susceptibility to ten categories of antibacterial agents was assessed using the Kirby-Bauer method according to the Clinical and Laboratory Standards Institute M100 guidelines (2021). The MIC of glycopeptides was determined using the broth microdilution test. Results: Among methicillin-resistant S. aureus isolates (40.8%), the majority were from patients with impetigo (53.92%). The highest resistance rate was observed against penicillin (79.41%) and doxycycline (73.52%). Linezolid showed significant inhibitory properties against XDR (91%) and MDR (97%) S. aureus isolates (P = 0.01). The MIC of oritavancin that inhibited the growth of 90% of the MDR isolates (MIC90) was 2 µg/mL, which was eight times less than that of vancomycin (MIC90 = 16 µg/mL) and 16 times lower than that of teicoplanin (MIC90 = 32 µg/mL) in a manner that 91% of MDR isolates from impetigo were eliminated at concentrations 2 µg/mL. Oritavancin inhibited the growth of 54.5% of XDR isolates at MIC concentrations of ≥8 µg/mL. Conclusions: Considering the strong antibacterial activity of linezolid against MDR S. aureus isolates, this antibiotic can effectively treat skin infections caused by S. aureus and prevent the development of resistance to other antibiotics. In addition, considering the great inhibitory properties of oritavancin against MDR S. aureus strains, the efficacy of this agent for treating skin infections, particularly impetigo, should be investigated.

Assessment of synergistic activity of rhamnolipid and linezolid against methicillin-resistant Staphylococcus aureus in-vitro and in-vivo with Galleria mellonella larvae model.

Antibiotic resistance, one of the most crucial public health problems, has increased the interest in synergy studies of antibiotics with existing antibiotics and natural compounds to make current treatment more effective in addition to new drug development. In this study, the effectiveness of rhamnolipid and linezolid on the Galleria mellonella larvae model in-vitro and in-vivo against Methicillin-resistant Staphylococcus aureus isolates, which are problematic in treatment, were investigated. Four S.aureus (One ATCC 29213 strain and three methicillin-resistant strains) were used in the study. Two MRSA isolates were resistant to linezolid, and one was susceptible. Partial synergy was observed in one resistant strain, and although no synergy was observed in the other resistant strain, the minimum inhibitory concentration of the resistant strain decreased from 16 to 4μg/mL with a four-fold decrease and reached the susceptibility limit. No change was observed in the MIC of linezolid-susceptible strains. The G.mellonella larval model demonstrated that combined therapy was more effective than monotherapy by survival function tests and CFU determination. RML/LNZ combination improved survival compared to monotherapy and decreased the bacterial burden from 108 to 103.

1696. Comparison of in vitro activities of linezolid and contezolid against clinical Nocardia isolates

Abstract Background Nocardia is nearly 100% susceptible to linezolid which is one of the first-line agents for all clinical species and isolates reported in the literature. However, adverse reactions related to myelosuppression and monoamine oxidase inhibition have limited linezolid use to some extent. Contezolid, a new oxazolidinone antibiotic that has decreased toxicity compared to linezolid, was launched in China in June 2021. In this study, the in vitro activities of linezolid and contezolid are compared against Nocardia. Methods Ninety-four clinical Nocardia isolates from Beijing Chao-Yang Hospital were identified by multilocus sequence analysis, and the in vitro activities of linezolid and contezolid were evaluated using the broth microdilution method. A Wilcoxon Signed Rank Test was performed to determine if linezolid and contezolid are significantly different from each other against clinical Nocardia isolates. Results Pulmonary nocardiosis (91.5%) was the most common clinical presentation of Nocardia infections. N. cyriacigeorgica (36.2%) and N. farcinica (16.0%) were the most frequently encountered Nocardia species, followed by N. abscessus (9.6%) and N. otitidiscaviarum (9.6%). The MIC (minimum inhibitory concentration) ranges of all clinical Nocardia isolates for linezolid and contezolid were 0.5-8 μg/mL. The MIC50/MIC90 values for all isolates of Nocardia for linezolid vs contezolid was 2/4 μg/mL vs 2/4 μg/mL, and for N. cyriacigeorgica and N. farcinica were 4/4 μg/mL vs 2/4 μg/mL and 4/4μg/mL vs 2/4 μg/mL, respectively. After a Wilcoxon Signed Rank Test analysis, the P values of all Nocardia isolates was < 0.001, and for N. cyriacigeorgica and N. farcinica were 0.001 and 0.020, respectively. Conclusion Though MIC50/MIC90 values for linezolid and contezolid for all Nocardia isolates evaluated appeared to be similar, there was a statistically significant difference between the two antibiotics. Furthermore, the MIC50 values for the most commonly encountered species N. cyriacigeorgica and N. farcinica were lower for contezolid than for linezolid. Therefore, the in vitro activity of contezolid is better than that of linezolid against clinical Nocardia isolates, and contezolid could also be an option for the treatment of Nocardia infections. Disclosures All Authors: No reported disclosures.

Novel oxazolidinones harbor potent in vitro activity against the clinical isolates of multidrug-resistant Mycobacterium tuberculosis in China.

To investigate the in vitro activities of five oxazolidinones in parallel against the reference strains of different mycobacterial species and clinical isolates of Mycobacterium tuberculosis (Mtb), and shed light on the differences in the efficacy of these homolog drugs. The minimum inhibitory concentrations (MICs) of linezolid, tedizolid, sutezolid, delpazolid, and contezolid against 16 mycobacterial reference strains and 69 M. tuberculosis clinical isolates, including 17 drug-susceptible isolates and 52 multidrug-resistant (MDR) isolates, were determined by microplate alamarBlue assay (MABA). The intracellular killing activities of contezolid and linezolid against Mtb H37Rv were compared. In addition, mutations in the linezolid resistance-related genes (rplC, rplD, and 23S rRNA) of the Mtb clinical isolates were also analyzed. Tedizolid exhibited the strongest inhibitory activities against the reference strains of both rapidly growing mycobacteria (RGM) and slowly growing mycobacteria (SGM), among the tested oxazolidinones. In contrast, sutezolid only manifested potent activity against reference strains of SGM. Linezolid, delpazolid, and contezolid were less active against the non-tuberculous mycobacterial references. For the Mtb clinical isolates, the antimicrobial action was ranked as: sutezolid > tedizolid > contezolid and linezolid > delpazolid, whereas no difference between drug-sensitive and multiple drug-resistant isolates was observed. Notably, contezolid demonstrated obviously superior intracellular antimicrobial activity than linezolid. Few strains harbored mutations in rrl gene or rplD genes, although these strains had drug susceptible profiles to linezolid. Different oxazolidinones can have discrepant antimicrobial activity against different mycobacterial species, or have different manifestations out of cell or in cell. Understanding these differences would be helpful in choosing the appropriate drug in clinical practice.

Antibacterial Efficacy of Linezolid Alone and in Combination with Zinc Oxide Nanoparticles against Methicillin-Resistant S. Aureus Clinical Isolates

Skin and soft tissue infections caused by methicillin-resistant S. aureus (MRSA) are among the most common bacterial infections. Linezolid is a cortisone drug for the treatment of infections caused by MRSA. However, developing resistance to linezolid creates a hurdle in the treatment of these infections. The present study aimed to determine the activity of linezolid alone and in combination with zinc oxide nanoparticles (ZnO-NPs) for the purpose of reducing resistance and enhancing its efficacy. For this study, MRSA isolates were taken and confirmed by using the antibiotic susceptibility testing method. The minimum inhibitory concentration (MIC) of both antibiotics and nanoparticles against MRSA clinical isolates was done by using the broth microdilution method. A checkerboard assay has used the determination of the combined activity of linezolid and ZnO-NPs. ZnO-NPs displayed a spherical shape with smooth surface morphology and had a mean size of 10 nm to 20 nm, with a zeta potential of 3.57 mV. The activity of ZnO-NPs against MRSA clinical isolates was 200 µg/ml. Almost 81% of isolates were found sensitive to linezolid with MIC lower than 4 µg/ml, and 19% were resistant, having MIC greater than 4 µg/ml. The combination of an antibiotic and nanoparticles reduced the activity of each of them twofold. The current study revealed that both linezolid and ZnO-NPs have antimicrobial activity against MRSA when used alone. The combination of both medications reduces each other's MIC twofold and has an antagonistic impact. Further research is needed to determine the mechanism through which these medications inhibit each other's activity.

Comparative study of in vitro activity of tedizolid and linezolid against Mycobacterium avium complex.

ObjectivesThe aim of this study is to compare the in vitro activity and minimal inhibitory concentration (MIC) distributions of tedizolid and linezolid against Mycobacterium avium complex (MAC) strains using a reference broth microdilution assay and a macrodilution assay with the Bactec-MGIT-960. MethodsA total of 37 clinical isolates of MAC were included in the study. Reference broth microdilution was performed according to CLSI guidelines in a range of concentrations from 64 to 0.064 mg/L. Macrodilution was performed with the Bactec-MGIT-960 system. The cut-off points defined by CLSI for linezolid (resistant: > 16 mg/L, intermediate: 16 mg/L, susceptible: <16 mg/L) were used to define clinical categories of this drug. Essential agreement for both linezolid and tedizolid and categorical agreement for linezolid were defined following FDA criteria. ResultsThe MIC50 (16mg/L) and MIC90 (32mg/L) values for linezolid were identical with both methods. However, the MIC50 and MIC90 of tedizolid by microdilution (4 mg/L and 8 mg/L, respectively) were one twofold dilution higher than by macrodilution (2 mg/L and 4 mg/L, respectively). Ninety-four percent and 2.7% of the strains had MICs of tedizolid ≤4 mg/L and ≤ 0.5 mg/L, respectively, by the reference method. The linezolid macrodilution assay showed a categorical agreement of 40.5%, a minor error rate of 56.7% and a major error rate of 2.7% with respect to the reference method. ConclusionsTedizolid showed higher in vitro activity than linezolid against the tested MAC isolates. Macrodilution using the BD Bactec-MGIT-960 system is a practical approach to determine the susceptibility of MAC strains to tedizolid.

Antibiotic sensitivity analysis of clinical coagulase-negative staphylococci

Background. The increasing role of coagulase-negative staphylococci in the occurrence of staphylococcal infections leads to the need for close attention to them. Special control is required over the sensitivity of bacteria to antibiotics and the spread of methicillin resistance, as a sign of multiple resistance to antibacterial drugs. It is also important to identify the virulence factors of coagulase-negative staphylococci, which determine their behavior in the environment.The aim. To evaluate the sensitivity of strains of coagulase-negative staphylococci to clinically significant antibiotics daptomycin, vancomycin, linezolid and oxacillin and lantibiotic warnerin.Methods. Determination of the minimal inhibitory concentrations of antibacterial compounds for clinical coagulase-negative staphylococci by standard methods of serial dilutions and disc diffusion. Identification of the phenomenon of decreased susceptibility of bacteria to vancomycin by population analysis and concentration gradient. Lipid analysis by thin layer chromatography. Results. High antibacterial activity of vancomycin, daptomycin and linezolid against clinical strains of coagulase-negative staphylococci was shown. The upper limit of the minimum inhibitory concentrations of vancomycin within the sensitive phenotype and the expansion of the ranges of the minimum inhibitory concentrations of daptomycin and warnerin towards an increase in oxacillin-resistant isolates were revealed. The heterogeneous nature of sensitivity to vancomycin of the cultures of the studied strains and the possibility of their rapid enrichment with subpopulations with reduced sensitivity to this antibiotic have been established. The selection of resistance of coagulase-negative staphylococci to vancomycin was accompanied by an increase in the synthesis of lysylphosphatidylglycerol and a decrease in their sensitivity to cationic peptide compounds.Conclusion. The revealed prevalence of the methicillin-resistant phenotype of clinical strains of coagulase-negative staphylococci, along with the presence in the lipid spectrum of the universal factor of resistance to cationic antibacterial compounds, lysylphosphatidylglycerol, entails the need for new methodological solutions for diagnosing infections caused by coagulase-negative staphylococci.

In vitro activity of tedizolid and linezolid against multidrug-resistant Mycobacterium tuberculosis: a comparative study using microdilution broth assay and genomics

The effects of tedizolid (TZD) against multidrug-resistant Mycobacterium tuberculosis isolates were investigated. This is possibly the first study to evaluate the MIC of TZD against Japanese Mycobacterium tuberculosis isolates. As TZD had a significantly lower MIC than LZD (P < 0.01), it was suggested to be a better, non-toxic alternative to LZD.

Comparison of Anti-Microbic and Anti-Biofilm Activity Among Tedizolid and Radezolid Against Linezolid-Resistant Enterococcus faecalis Isolates.

BackgroundThe emergence and spread of linezolid-resistant Enterococcus faecalis (E. faecalis) have emerged as a serious threat to human health globally. Therefore, this study aims to compare the anti-microbic as well as the anti-biofilm activity of linezolid, tedizolid, and radezolid against linezolid-resistant E. faecalis.MethodsA total of 2128 E. faecalis isolates were assessed from the First Affiliated Hospital of Wenzhou Medical University from 2011 to 2019. Antibiotic sensitivity was evaluated using the micro broth dilution method. Oxazolidinone-resistant chromosomal and plasmid-borne genes such as cfr, cfr(A), cfr(B), cfr(C), cfr(D), optrA, and poxtA were detected by PCR and then sequenced to detect the presence of mutations in the domain V of the 23S rRNA and the ribosomal proteins L3, L4, and L22. Conjugation experiments were conducted using the broth method. The inhibition and eradication of biofilm were evaluated through crystal violet staining, whereas the efflux pump activities were detected by agar dilution.ResultsOut of 2128 isolated E. faecalis, 71 (3.34%) were linezolid-resistant isolates in which the MICs of tedizolid and radezolid ranged from 1 to 4 μg/mL and 0.5–1 μg/mL, respectively. The MIC50/MIC90 of tedizolid and radezolid were 4 and 8-fold lower than the linezolid, respectively. Out of 71 resistant isolates, 57 (80.28%) carried optrA, 1 (1.41%) carried cfr, 4 (5.63%) carried optrA and cfr, and 6 (8.45%) carried optrA and cfr(D), with no mutations of 23S rRNA gene and ribosomal proteins L3, L4, and L22. Besides, the transfer rate of the optrA, cfr, and cfr(D) was 17.91%, 0% and 0%, respectively. Radezolid showed more effectiveness in eradicating biofilm (8 × MIC). However, tedizolid was more effective than radezolid and linezolid in inhibiting the biofilm formation (1/4 MIC, 1/8MIC, and 1/16MIC). Additionally, in combination with CCCP, the MICs of radezolid in all linezolid-resistant isolates decreased ≥4-fold.ConclusionRadezolid showed greater antimicrobial activity than tedizolid and linezolid against linezolid-resistant E. faecalis. However, both tedizolid and radezolid showed differential activity on biofilm inhibition, eradication, and efflux pump compared to linezolid. Thus, our study might bring important clinical value in the application of these drugs for resistant pathogenic strains.

COMPARATIVE ANALYSIS OF THE ACTIVITY OF GLYCOPEPTIDES AND LINEZOLID AGAINST NOSOCOMIAL STRAINS OF GRAM-POSITIVE MICROORGANISMS ISOLATED FROM CANCER PATIENT

The purpose of the study: to compare the activity of vancomycin, teicoplanin and linezolid and to determine their place in the current treatment of nosocomial infections caused by gram-positive microflora.Material and Methods. 640 gram-positive microorganisms (S. aureus, E. faecium, E. faecalis) isolated in 2018 from various pathological materials from cancer patients treated at N.N. Blokhin National Medical Research Center of Oncology were studied. Literature data from 1982 to 2019, concerning efficacy of glycopeptides (vancomycin, teicoplanin) and linezolid against these pathogens were analyzed.Results. Data analysis showed that percentage of methicillin-resistant Staphylococcus aureus (MRSA) was 89 % and percentage of vancomycinresistant enterococci (VRE) was 5.1 % among Enterococcus faecalis and 16.4 % among Enterococcus faecium. The susceptibility of the studied gram-positive microorganisms to teicoplanin, vancomycin and linezolid ranged from 83.3 to 98.8 % (p&gt;0.5). In general, teicoplanin, vancomycin, and linezolid had equally high microbiological activity against nosocomial strains of S. aureus and Enterococcus spp. Also, according to the literature data, a comparative assessment of the clinical effectiveness and cost-effectiveness of glycopeptides and linezolid was assessed.Conclusion. Vancomycin and teicoplanin are still the main drugs for the treatment of various infections caused by resistant gram-positive microflora. However, teicoplanin, with an efficacy equal to that of vancomycin, has a number of significant advantages over the latter: better tolerability, lower frequency of adverse reactions, and pharmacokinetic features that make it possible to use it once a day both intravenously and intramuscularly. Both drugs, along with linezolid, can be used to treat infections caused by gram-positive microorganisms in cancer patients.

Potential activity of Linezolid against SARS-CoV-2 using electronic and molecular docking study.

The crescent evolution of a global pandemic COVID-19 and its respiratory syndrome (SARS-Cov-2) has been a constant concern (Ghosh 2021; Khan et al. 2021; Alazmi and Motwalli 2020; Vargas et al. 2020). The absence of a proven and effective medication has compelled all the scientific community to search for a new drug. The use of known drugs is a faster way to develop new therapies. Molecular docking is a powerful tool (Gao et al. J Mol Model 10: 44–54, 2004; Singh et al. J Mol Model 18: 39–51, 2012; Schulz-Gasch and Stahl J Mol Model 9:47–57, 2003) to study the interaction of potential drugs with SARS-CoV-2, Alsalme et al. (2020) and Sanders et al. (2020) spike protein as a consequence the main goal of this article is to present the result of the study of an interaction between (R and S)-Linezolid with receptor-binding domain (RBD) of SARS-Cov-2 spike protein complexed with human Angiostensin-converting enzyme 2 (ACE2) (6vW1 - from PDB). The Linezolid enantiomers were optimized at B3LYP/6-311++G(2d,p) level of theory. Molecular docking of the system (S)-Linezolid⋯RBD⋯ACE2 and (R)-Linezolid⋯RBD⋯ACE2 was performed, the analysis was made using LigPlot+ and NCIplot software packages, to understand the intermolecular interactions. The UV-Vis and ECD of the complexes - (R and S)-Linezolid⋯RBD⋯ACE2 were performed in two layers with DFT/6-311++G(3df,2p) and DFT/6-31G(d), respectively. The results showed that only the (S)-Linezolid had a stable interaction with − 8.05 kcal.mol− 1, whereas all the R-enantiomeric configurations had positive values of binding energy. The (S)-Linezolid had the same interactions as in the (S)-Linezolid ⋯ Haluarcula morismortui Ribosomal system, where it is well-known the fact that the latter has biological activity. A specific interaction on the fluorine ring justified an attenuation on the ECD signal, in comparison to isolated species. Therefore, some biological activity of (S)-Linezolid with SARS-CoV-2 RBD was expected, indicated by the modification of its ECD signal and justified by a similar interaction in the S-Linezolid⋯Haluarcula marismortui Ribosomal system.Supplementary informationThe online version contains supplementary material available at 10.1007/s00894-021-04828-8.

Comparison of the in vitro activity of linezolid, tedizolid, sutezolid, and delpazolid against rapidly growing mycobacteria isolated in Beijing, China

BackgroundThe natural resistance of rapidly growing mycobacteria (RGM) to multiple antibiotics renders the treatment of the infections caused less successful. The objective of this study was to evaluate the in vitro susceptibilities of four oxazolidinones against different RGM species. MethodsThe microplate alamarBlue assay was performed to identify the minimum inhibitory concentrations (MICs) of four oxazolidinones – delpazolid, sutezolid, tedizolid, and linezolid – for 32 reference strains and 115 clinical strains of different RGM species. The MIC breakpoint concentration was defined as 16 μg/ml for linezolid. Next, the gene fragments associated with oxazolidinone resistance were amplified and sequenced, and mutations were defined in contrast with the sequences of the reference strains. ResultsTedizolid showed the strongest inhibitory activity against the Mycobacterium abscessus isolates. Delpazolid exhibited better antimicrobial activity against the Mycobacterium fortuitum isolates when compared to linezolid, with 4-fold lower MIC values. The protein alignment and structure-based analysis showed that there might be no correlation between oxazolidinone resistance and mutations in the rplC, rplD, and 23S rRNA genes in the tested RGM. ConclusionsTedizolid had the strongest inhibitory activity against M. abscessus in vitro, while delpazolid presented the best inhibitory activity against M. fortuitum. This provides important insights into the potential clinical application of oxazolidinones to treat RGM infections.

Antimicrobial Surveillance for Bacterial Uropathogens in Ha'il, Saudi Arabia: A Five-Year Multicenter Retrospective Study.

ObjectiveUrinary tract infections (UTIs) are among the most common infections that require antibiotic intervention. Antibiotic surveillance programs are crucial to assess resistance patterns of microorganisms associated with UTIs and to tailor antibiotic therapy accordingly. Therefore, the aim of the current study is to investigate the prevalence of uropathogens and their antimicrobial susceptibility patterns in Ha’il region.MethodsWe conducted a retrospective study in two main hospitals in Ha’il over a 5-year period (January 2015 to December 2019). Laboratory reports and clinical data of patients with a positive urine culture (≥105 CFU/mL) were included in the study.ResultsA total of 428 patients were included in this study. The majority of positive cultures belonged to female patients (94.4%), adults (76.9%) and outpatients (74.3%). Generally, Escherichia coli was the most common pathogen (45%), followed by Klebsiella pneumoniae (17%) and Staphylococcus aureus (12%). Extended-spectrum β-lactamase (ESBL) strains of E. coli (15.7%) and K. pneumoniae (19.7%) showed resistance to most tested antibiotics, while almost all Gram-negative uropathogens including ESBL strains presented low resistance to cefoxitin, imipenem and meropenem. Most strains of Staphylococcus aureus and Enterococcus faecalis were resistant to trimethoprim/sulfamethoxazole including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE), whereas the activity of linezolid was monitored against almost all different strains of Gram-positive uropathogens.ConclusionThis surveillance study which was conducted over a 5-year period in the Ha’il region revealed that the most common UTI-associated pathogen was E. coli. Based on the current sensitivity profiles obtained from this surveillance, carbapenems and linezolid can be considered as a first therapeutic choice treating UTIs in Ha’il caused by Gram-negative and positive uropathogens, respectively. Frequent targeted surveillance programs for antibiotic-resistant pathogens and their susceptibility profiles are crucial to enable tailored empirical treatment for patients.

In vitro and in vivo Antibacterial Activity of Linezolid Plus Fosfomycin Against Staphylococcus aureus with Resistance to One Drug.

ObjectiveThe purpose of this study is to assess the in vitro/vivo activities of linezolid plus fosfomycin against Staphylococcus aureus (S. aureus) isolates with varying susceptibility to the study drugs.MethodsThe increasing concentration stepwise method was used to induce S. aureus resistant strains. The in vitro antibacterial activity of linezolid combined with fosfomycin against S. aureus in vitro was studied by time-kill curve and PAE. The transmission electron microscopy (TEM) was employed to observe the cell morphology of bacteria treated with drug, and the changes of cell wall thickness were recorded. The Galleria mellonella infection model was established to demonstrate the in vivo efficacy of linezolid and fosfomycin against S. aureus with varying susceptibility.ResultsThe antibiotic combination showed excellent synergistic or additive effects on the original and the linezolid-resistant strain, but showed indifferent effect for fosfomycin-resistant strain. TEM images showed that fosfomycin alone and in combined could reduce the cell wall thickness of the strains resistant to linezolid and cell lysis, while linezolid increases the cell wall thickness of the strains resistant to fosfomycin. In the Galleria mellonella infection model, the survival rate of the antibiotic combined was improved compared with that of the single drug. There was a good correlation between in vivo efficacy and in vitro susceptibility.ConclusionThe type of interaction expressed in the test combination was highly dependent on fosfomycin resistance.

Optimization of Linezolid Dosing Regimens for Treatment of Vancomycin-Resistant Enterococci Infection.

BackgroundLinezolid, an oxazolidinone antibiotic, is recommended for vancomycin-resistant enterococci (VRE). However, 100% free-drug concentration above the minimum inhibitory concentration (fT>MIC) and an area under the curve of free drug to MIC ratio (fAUC24/MIC) >100 were associated with favorable clinical outcome with less emerging resistance. A plasma trough concentration (Ctrough) of linezolid ≥9 µg/mL was also related to hematologic toxicity. Thus, linezolid dose optimization is needed for VRE treatment. The study aimed to determine the in vitro linezolid activity against clinical VRE isolates and linezolid dosing regimens in critically ill patients who met the target pharmacokinetics/pharmacodynamics (PK/PD) for VRE treatment.Materials and MethodsEnterococcal isolates from enterococcal-infected patients were obtained between 2014 and 2018 at Phramongkutklao Hospital. We used Monte Carlo simulation to calculate the probability of target attainment, and the cumulative fraction of response (CFR) of the free area under the curve to MIC ratio (fAUIC24) was used to calculate the fAUC24/MIC 80 - 100 and fT/MIC >85 - 100% of the interval time of administration for clinical response and microbiological eradication as well as the Ctrough ≥9 µg/mL for the probability of hematologic toxicity.ResultsFor linezolid MIC determination, the MIC median (MIC50), MIC for 90% growth (MIC90), and range for linezolid were 1.5 µg/mL, 2 µg/mL, and 0.72 - 2 µg/mL, respectively. A dosing regimen of 1,200 mg either once daily or as a divided dose every 12 h gave target attainments of fAUC24/MICs >80 and >100, which exceeded 90% for MICs ≤1 and ≤1 µg/mL, respectively, with a rate of hematologic toxicity <15%. If the expected fT>MICs were >85% and 100%, a 1,200-mg divided dose every 12 h could cover VRE isolates having linezolid MICs ≤1 µg/mL and ≤0.75 µg/mL. Even 600 mg every 8 h and 1,200 mg as a continuous infusion gave a higher target attainment of fAUC24/MIC and a fT>MIC and the target CFR, but those regimens gave Ctrough ≥9 µg/mL rates of 40.7% and 99.6%.ConclusionThe current dosing of 1,200 mg/day might be optimal treatment for infection by VRE isolates with documented MICs ≤1 µg/mL. For treatment of VRE with a MIC of 2 µg/mL or to achieve the target CFR, the use of linezolid with other antibiotic combinations might help achieve the PK/PD target, provide better clinical outcome, and prevent resistance.

Antibacterial Activity of Linezolid against Gram-Negative Bacteria: Utilization of ε-Poly-l-Lysine Capped Silica Xerogel as an Activating Carrier.

In recent times, many approaches have been developed against drug resistant Gram-negative bacteria. However, low-cost high effective materials which could broaden the spectrum of antibiotics are still needed. In this study, enhancement of linezolid spectrum, normally active against Gram-positive bacteria, was aimed for Gram-negative bacteria growth inhibition. For this purpose, a silica xerogel prepared from a low-cost precursor is used as a drug carrier owing to the advantages of its mesoporous structure, suitable pore and particle size and ultralow density. The silica xerogel is loaded with linezolid and capped with ε-poly-l-lysine. The developed nano-formulation shows a marked antibacterial activity against to Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. In comparison to free linezolid and ε-poly-l-lysine, the material demonstrates a synergistic effect on killing for the three tested bacteria. The results show that silica xerogels can be used as a potential drug carrier and activity enhancer. This strategy could provide the improvement of antibacterial activity spectrum of antibacterial agents like linezolid and could represent a powerful alternative to overcome antibiotic resistance in a near future.