scholarly journals Balancing the stability and drug activation in adaptive nanoparticles potentiates chemotherapy in multidrug-resistant cancer

Theranostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 4137-4154
Author(s):  
Jianqin Wan ◽  
Lingling Huang ◽  
Jiangting Cheng ◽  
Huangfu Qi ◽  
Jiahui Jin ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
The Stability ◽  
Drug Activation

scholarly journals Influence of the α-Methoxy Group on the Reaction of Temocillin with Pseudomonas aeruginosa PBP3 and CTX-M-14 β-Lactamase

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Michael D. Sacco ◽  
Kyle G. Kroeck ◽  
M. Trent Kemp ◽  
Xiujun Zhang ◽  
Logan D. Andrews ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Active Site ◽  
Methoxy Group ◽  
Complex Structure ◽  
Antibacterial Properties ◽  
Multidrug Resistant ◽  
Binding Modes ◽  
Content Type ◽  
The Stability ◽  
M 14

ABSTRACT The prevalence of multidrug-resistant Pseudomonas aeruginosa has led to the reexamination of older “forgotten” drugs, such as temocillin, for their ability to combat resistant microbes. Temocillin is the 6-α-methoxy analogue of ticarcillin, a carboxypenicillin with well-characterized antipseudomonal properties. The α-methoxy modification confers resistance to serine β-lactamases, yet temocillin is ineffective against P. aeruginosa growth. The origins of temocillin’s inferior antibacterial properties against P. aeruginosa have remained relatively unexplored. Here, we analyze the reaction kinetics, protein stability, and binding conformations of temocillin and ticarcillin with penicillin-binding protein 3 (PBP3), an essential PBP in P. aeruginosa. We show that the 6-α-methoxy group perturbs the stability of the PBP3 acyl-enzyme, which manifests in an elevated off-rate constant (koff) in biochemical assays comparing temocillin with ticarcillin. Complex crystal structures with PBP3 reveal similar binding modes of the two drugs but with important differences. Most notably, the 6-α-methoxy group disrupts a high-quality hydrogen bond with a conserved residue important for ligand binding while also being inserted into a crowded active site, possibly destabilizing the active site and enabling water molecule from bulk solvent to access and cleave the acyl-enzyme bond. This hypothesis is supported by the observation that the acyl-enzyme complex of temocillin has reduced thermal stability compared with ticarcillin. Furthermore, we explore temocillin’s mechanism of β-lactamase inhibition with a high-resolution complex structure of CTX-M-14 class A serine β-lactamase. The results suggest that the α-methoxy group prevents hydrolysis by locking the compound into an unexpected conformation that impedes access of the catalytic water to the acyl-enzyme adduct.

scholarly journals Antibiotic Activity Potentiation and Physicochemical Characterization of the Fixed Orbignya speciosa Almond Oil against MDR Staphylococcus aureus and Other Bacteria

Antibiotics ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 28 ◽  
Author(s):  
Jean Machado ◽  
Maria do Socorro Costa ◽  
Saulo Tintino ◽  
Fábio Rodrigues ◽  
Camila Nobre ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Physicochemical Characterization ◽  
Multidrug Resistant ◽  
Antagonistic Effect ◽  
Resistant Bacteria ◽  
Composition Analysis ◽  
Palm Tree ◽  
Almond Oil ◽  
Popular Medicine ◽  
The Stability

Orbignya speciosa (babassu) is an important palm tree in Brazil whose fixed almond oil is used in popular medicine and especially in food, in addition to being a research target for the manufacture of biofuels. The aim of this study was to evaluate the fixed almond oil physicochemical characterization and its antibacterial activity in isolation and in association with aminoglycosides against standard and multidrug-resistant bacteria. Analyses such as water content, pH, acidity, peroxide index, relative density, and refractive index indicate the stability and chemical quality of the oil. In the oil’s GC/MS chemical composition analysis, a high saturated fatty acid (76.90%) content was observed. Lauric acid (56.28%) and oleic acid (23.10%) were the major oil components. In the antibacterial test, a more significant oil activity was observed against K. pneumoniae KP-ATCC 10031 (minimal inhibitory concentration (MIC) = 406.37 μg/mL) and Staphylococcus aureus ATCC 6538 (MIC = 812.75 μg/mL), but for the other strains—including standard and multi-resistant strains—the oil presented an MIC ≥ 1024 μg/mL. Furthermore, a synergistic effect was observed when the oil was associated with amikacin and gentamicin against S. aureus (SA-10) and an antagonistic effect was observed with amikacin against Escherichia coli. Data indicate the O. speciosa oil as a valuable nutritional source of lauric, oleic, and myristic fatty acids with an ability to modulate aminoglycoside activity.

scholarly journals Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin

2009 ◽  
Vol 53 (8) ◽  
pp. 3496-3500 ◽  
Author(s):  
Darren J. Creek ◽  
Eileen Ryan ◽  
William N. Charman ◽  
Francis C. K. Chiu ◽  
Richard J. Prankerd ◽  
...  
Keyword(s):  
Spectroscopic Analysis ◽  
Protein Denaturation ◽  
Reactive Intermediates ◽  
Multidrug Resistant ◽  
Potential Interaction ◽  
Human Hemoglobin ◽  
Selective Toxicity ◽  
Artemisinin Derivatives ◽  
Free Heme ◽  
The Stability

ABSTRACT Peroxide antimalarials, including artemisinin, are important for the treatment of multidrug-resistant malaria. These peroxides are known to react with iron or heme to produce reactive intermediates that are thought to be responsible for their antimalarial activities. This study investigated the potential interaction of selected peroxide antimalarials with oxyhemoglobin, the most abundant form of iron in the human body. The observed stability of artemisinin derivatives and 1,2,4-trioxolanes in the presence of oxyhemoglobin was in contrast to previous reports in the literature. Spectroscopic analysis of hemoglobin found it to be unstable under the conditions used for previous studies, and it appears likely that the artemisinin reactivity reported in these studies may be attributed to free heme released by protein denaturation. The stability of peroxide antimalarials with intact oxyhemoglobin, and reactivity with free heme, may explain the selective toxicity of these antimalarials toward infected, but not healthy, erythrocytes.

scholarly journals A Systematic Study of the Stability, Safety, and Efficacy of the de novo Designed Antimicrobial Peptide PepD2 and Its Modified Derivatives Against Acinetobacter baumannii

2021 ◽  
Vol 12 ◽  
Author(s):  
Sung-Pang Chen ◽  
Eric H-L Chen ◽  
Sheng-Yung Yang ◽  
Pin-Shin Kuo ◽  
Hau-Ming Jan ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Antimicrobial Peptide ◽  
Acinetobacter Baumannii ◽  
De Novo ◽  
Multidrug Resistant ◽  
Hek293 Cells ◽  
Amino Acid Residues ◽  
Bacteria And Fungi ◽  
The Stability

Searching for new antimicrobials is a pressing issue to conquer the emergence of multidrug-resistant (MDR) bacteria and fungi. Antimicrobial peptides (AMPs) usually have antimicrobial mechanisms different from those of traditional antibiotics and bring new hope in the discovery of new antimicrobials. In addition to antimicrobial activity, stability and target selectivity are important concerns to decide whether an antimicrobial peptide can be applied in vivo. Here, we used a simple de novo designed peptide, pepD2, which contains only three kinds of amino acid residues (W, K, L), as an example to evaluate how the residues and modifications affect the antimicrobial activity against Acinetobacter baumannii, stability in plasma, and toxicity to human HEK293 cells. We found that pepI2 with a Leu→Ile substitution can decrease the minimum bactericidal concentrations (MBC) against A. baumannii by one half (4 μg/mL). A D-form peptide, pepdD2, in which the D-enantiomers replaced the L-enantiomers of the Lys(K) and Leu(L) residues, extended the peptide half-life in plasma by more than 12-fold. PepD3 is 3-residue shorter than pepD2. Decreasing peptide length did not affect antimicrobial activity but increased the IC50 to HEK293 cells, thus increased the selectivity index (SI) between A. baumannii and HEK293 cells from 4.7 to 8.5. The chain length increase of the N-terminal acyl group and the Lys→Arg substitution greatly enhanced the hemolytic activity, hence those modifications are not good for clinical application. Unlike colistin, the action mechanism of our peptides relies on negatively charged lipids rather than lipopolysaccharides. Therefore, not only gram-negative bacteria but also gram-positive bacteria can be killed by our peptides.

scholarly journals On network suppression of multidrug-resistant pathogen spread

2021 ◽  
Author(s):  
Monika Piotrowska ◽  
Aleksandra Puchalska ◽  
Konrad Sakowski
Keyword(s):  
Healthcare System ◽  
Sufficient Conditions ◽  
Numerical Procedure ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Insurance Company ◽  
Lower Saxony ◽  
Real Patient ◽  
Healthcare Facilities ◽  
The Stability

In the paper we present a system of SIS type equations coupled by impulses at fixed times that describe the transfer of patients in the healthcare system represented by a graph of healthcare facilities and corresponding communities. The first aim for this considerations is to provide rigorous mathematical analysis of a general theoretical model, which is then used to model transmission of hospital acquired multidrug-resistant bacteria infections based on real patient hospital records provided by German insurance company – AOK Lower Saxony. Starting from the existence and the asymptotic behaviour, together with specification of parameter R, we propose sufficient conditions guaranteeing network suppression of infection. Furthermore, conditions derived analytically and proposed numerical procedure are used to indicate healthcare facilities that are most prone to the high prevalence bacteria spread in the healthcare system and to ensure the stability of disease-free steady state of the system.

scholarly journals Cyanidin-3-glucoside Lipophilic Conjugates for Topical Application: Tuning the Antimicrobial Activities with Fatty Acid Chain Length

Processes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 340
Author(s):  
Hélder Oliveira ◽  
Patrícia Correia ◽  
Lucinda J. Bessa ◽  
Marta Guimarães ◽  
Paula Gameiro ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Fatty Acid ◽  
Antioxidant Capacity ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Aliphatic Chain ◽  
Fatty Acid Chain ◽  
The Stability ◽  
Application Tuning ◽  
Chain Lengths

Background: Natural anthocyanins present a low solubility in lipophilic media, which compromises their effective application in lipophilic systems. In this work, cyanidin-3-O-glucoside (Cy3glc) was esterified by the addition of fatty acids with increasing chain-lengths and a structure-activity relationship was performed towards the description of the best analog for skin-care applications. Methods: By enzymatic hemi-synthesis, it was possible to obtain 5 structurally related derivatives of cyanidin-3-O-glucoside with successive C2 increments in the aliphatic chain. The stability in hanks buffer and DMEM with or without FBS was followed by HPLC. The cytotoxicity against keratinocytes was evaluated by MTT assay. The antioxidant capacity was determined by using the fluorescent probe DCF-DA. The effect on enzyme activity was evaluated towards tyrosinase, collagenase, and elastase enzymes by colorimetric assays. MIC and MBC values were obtained against reference strains and against multidrug-resistant isolates. Results: In physiological conditions, cy3glc−fatty acid derivatives are more stable and may be converted to the native anthocyanin. The 5 conjugates showed lower antioxidant capacity and enzymatic inhibitory activities in comparison to the anthocyanin precursor. However, concerning the antibacterial activity, the insertion of a fatty acid chain sprouted the antibacterial activity, showing a clear biphasic effect and a more effective effect on Gram-positive bacteria. Conclusions: Cy3glc-C10 was the most effective compound considering the antimicrobial activity, although a general reduction was observed among the other activities evaluated. This work prompt further assays with a different panoply of derivatives ranging other features including saturation vs. unsaturation, even vs. odd carbon content and linear vs. branched.

scholarly journals Application of Nanotechnology in Immunity against Infection

Coatings ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 430
Author(s):  
Jingxin Zhang ◽  
Weiyue Shi ◽  
Qiang Ma ◽  
Haixin Cui ◽  
Liang Zhang
Keyword(s):  
Infectious Diseases ◽  
Antimicrobial Agents ◽  
Antibacterial Effect ◽  
Multidrug Resistant ◽  
The Body ◽  
Particle Size Range ◽  
Important Means ◽  
The Stability ◽  
Treatment Of Infection ◽  
New Strategies

The immune system has a physiological defense function, protecting the body from infectious diseases. Antibiotics have long been one of the most important means to treat infectious diseases, but in recent years, with the emergence of more and more multidrug-resistant (MDR) bacteria, it has become urgent to find new ways or drugs to treat infectious diseases. Nanoparticles (NPs) have attracted extensive attention owing to the special properties within the particle size range of 1–100 nanometers. In addition, NPs also have special shape symmetry and relative structural stability. The emergence of nanotechnology has brought new light to the widespread existence of MDR by its different antibacterial mechanisms. In addition to antibiotic nanocarriers being able to improve the antibacterial effect of antibiotics, some NPs also have certain antibacterial effect. What is more interesting is that linking functional groups on the surface of NPS as coatings can improve the stability of the whole system and improve the biocompatibility. The present review overviews the development of antimicrobial agents, so as to better understand the causes and mechanisms of antibiotic resistance in most microbial species, and to better think and explore new strategies to solve the problem. At the same time, this review introduces how nanotechnology can be applied to anti-infection immunity and its practical application and advantages in the treatment of infection.

scholarly journals Instability of IS6110 patterns in multidrug-resistant strains of Mycobacterium tuberculosis

2006 ◽  
Vol 135 (2) ◽  
pp. 346-352 ◽  
Author(s):  
P. FARNIA ◽  
M. R. MASJEDI ◽  
B. NASIRI ◽  
M. MIRSAEDI ◽  
S. SOROOCH ◽  
...  
Keyword(s):  
Culture Media ◽  
Direct Repeat ◽  
Multidrug Resistant ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Lowenstein Jensen ◽  
Resistant Strains ◽  
Reliable Interpretation ◽  
The Stability

The stability of IS6110 restriction fragment length polymorphism (RFLP) pattern was determined in 31 isolates from patients with multidrug-resistant tuberculosis (MDR-TB). These patients were in actual chains of transmission and they referred to the National Institute of Tuberculosis and Lung Diseases, Tehran, Iran. Susceptibility testing against first- and second-line drugs were performed by the proportional method on Lowenstein–Jensen culture media. Thereafter, DNA fingerprinting by IS6110 with direct repeat (DR) region as a probe was performed by standard protocols. The rate of IS6110 changes was 16%, although, no variation was found in the DR region, in a time-span of 1–63 months. The strains with unstable IS6110 patterns were resistant to all drugs tested, and the majority of them (60%) were collected from HIV-positive patients. The results demonstrated that for a reliable interpretation of strain typing, it is better to use an additional marker along with IS6110 RFLP.

scholarly journals A Novel Structure Harboring blaCTX-M-27 on IncF Plasmids in Escherichia coli Isolated from Swine in China

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 387
Author(s):  
Yan Zhang ◽  
Yin-Huan Sun ◽  
Jiang-Yang Wang ◽  
Man-Xia Chang ◽  
Qiu-Yun Zhao ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Control Strategies ◽  
Multidrug Resistant ◽  
Farm Animals ◽  
The Novel ◽  
E Coli ◽  
Transmission Mechanisms ◽  
Novel Structure ◽  
Wide Range ◽  
The Stability

The aim of this study was to elucidate the prevalence of blaCTX-M-27-producing Escherichia coli and transmission mechanisms of blaCTX-M-27 from swine farms in China. A total of 333 E. coli isolates were collected from two farms from 2013 to 2016. Thirty-two CTX-M-27-positive E. coli were obtained, and all were multidrug-resistant. Pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) profiles indicated a wide range of strain types that carried blaCTX-M-27, and the sequence type ST10 predominated. Conjugation, replicon typing, S1-PFGE and hybridization experiments confirmed that 28 out of 32 CTX-M-27 positive isolates carried blaCTX-M-27 genes on plasmids F18:A-:B10 (16) and F24:A-:B1 (12).The blaCTX-M-27 genes for 24 isolates were transmitted by plasmids with sizes ranging from 40 to 155 kb. A comparative analysis with blaCTX-M-27-plasmids indicated that the tra-trb region of F24:A-:B1 plasmids was destroyed by insertion of a complex region (eight isolates) and a novel structure containing blaCTX-M-27 in the F18:A-:B10 plasmids (12 isolates). The novel structure increased the stability of the blaCTX-M-27 gene in E. coli. This study indicated that the predominant vehicle for blaCTX-M-27 transmission has diversified over time and that control strategies to limit blaCTX-M-27 transmission in farm animals are necessary.

scholarly journals Effect of physicochemical parameters on the stability and activity of garlic alliinase and its use for in-situ allicin synthesis

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248878
Author(s):  
Petra Janská ◽  
Zdeněk Knejzlík ◽  
Ayyappasamy Sudalaiyadum Perumal ◽  
Radek Jurok ◽  
Viola Tokárová ◽  
...  
Keyword(s):  
Chelating Agents ◽  
Storage Temperature ◽  
Multidrug Resistant ◽  
High Reactivity ◽  
Effect Of Temperature ◽  
Defence Mechanism ◽  
Bacterial Strains ◽  
The Stability ◽  
Self Defence

Garlic is a well-known example of natural self-defence system consisting of an inactive substrate (alliin) and enzyme (alliinase) which, when combined, produce highly antimicrobial allicin. Increase of alliinase stability and its activity are of paramount importance in various applications relying on its use for in-situ synthesis of allicin or its analogues, e.g., pulmonary drug delivery, treatment of superficial injuries, or urease inhibitors in fertilizers. Here, we discuss the effect of temperature, pH, buffers, salts, and additives, i.e. antioxidants, chelating agents, reducing agents and cosolvents, on the stability and the activity of alliinase extracted from garlic. The effects of the storage temperature and relative humidity on the stability of lyophilized alliinase was demonstrated. A combination of the short half-life, high reactivity and non-specificity to particular proteins are reasons most bacteria cannot deal with allicin’s mode of action and develop effective defence mechanism, which could be the key to sustainable drug design addressing serious problems with escalating emergence of multidrug-resistant (MDR) bacterial strains.

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