staphylococci

葡萄球菌
  • 文章类型: Journal Article
    对生物可降解植入物的兴趣已将注意力集中在可再吸收的聚合物聚乳酸上。然而,这些材料促进感染的风险,尤其是在现有病理的患者中,需要监控。细菌粘附培养基中与人类病理相关的化合物的富集可以帮助理解这些成分如何影响感染过程的发展。具体来说,这项工作评估了葡萄糖和酮体(在糖尿病背景下)对金黄色葡萄球菌对生物材料聚乳酸的粘附动力学的影响,采用不同的方法,并根据细菌表面的物理性质及其代谢活性讨论结果。酮症酸中毒和高血糖症(GK2)的组合似乎是最糟糕的情况:该系统随着时间的推移促进了细菌持续定植的状态,抑制粘附的固定相并加强细菌对表面的附着。此外,这些补充剂导致细菌的代谢活性显着增加。与非丰富媒体相比,在酮症酸中毒条件下生物膜形成加倍,当处于浮游状态时,是葡萄糖引发代谢活动,当仅存在酮组分时,这实际上被抑制。这两种信息都必须是互补的,才能理解真实系统中可能发生的事情,浮游细菌是最初在表面定殖的细菌,and,随后,这些附着的细菌最终形成了生物膜。这些信息突出了对糖尿病患者进行良好监测的必要性,特别是如果他们使用PLA制成的植入装置。
    Interest in biodegradable implants has focused attention on the resorbable polymer polylactic acid. However, the risk of these materials promoting infection, especially in patients with existing pathologies, needs to be monitored. The enrichment of a bacterial adhesion medium with compounds that are associated with human pathologies can help in understanding how these components affect the development of infectious processes. Specifically, this work evaluates the influence of glucose and ketone bodies (in a diabetic context) on the adhesion dynamics of S. aureus to the biomaterial polylactic acid, employing different approaches and discussing the results based on the physical properties of the bacterial surface and its metabolic activity. The combination of ketoacidosis and hyperglycemia (GK2) appears to be the worst scenario: this system promotes a state of continuous bacterial colonization over time, suppressing the stationary phase of adhesion and strengthening the attachment of bacteria to the surface. In addition, these supplements cause a significant increase in the metabolic activity of the bacteria. Compared to non-enriched media, biofilm formation doubles under ketoacidosis conditions, while in the planktonic state, it is glucose that triggers metabolic activity, which is practically suppressed when only ketone components are present. Both information must be complementary to understand what can happen in a real system, where planktonic bacteria are the ones that initially colonize a surface, and, subsequently, these attached bacteria end up forming a biofilm. This information highlights the need for good monitoring of diabetic patients, especially if they use an implanted device made of PLA.
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  • 文章类型: Journal Article
    兽医诊所表面上潜在致病细菌的存在可能是有问题的。在这项研究中,我们收集了拭子样本(Fisherbrand,带有斯图尔特液体介质的双运输拭子)和来自五个兽医康复诊所的水样。将拭子和水样运送到微生物实验室进行处理。在实验室,拭子用于接种Hardy'sCdiff香蕉肉汤(用于艰难梭菌[Cdiff])和五种不同类型的细菌生长培养基,包括HardyCHROMMRSA琼脂(耐甲氧西林金黄色葡萄球菌[MRSA]和假中介链球菌[SIM]),甘露醇盐琼脂(S.金黄色葡萄球菌[SA]),曙红亚甲蓝琼脂(肠[ENT]),假单胞菌分离琼脂(假单胞菌属。[PS]),和胰蛋白酶大豆琼脂[TSA](非特异性)。培养的最突出的推定物种是Cdiff(在近55%的拭子上)。芽孢杆菌。在近35%的拭子上遇到了肠道细菌,MRSA和SIM在10%以上的拭子上。污染最严重的样本地点是水下跑步机使用的安全带/救生衣(占拭子的33%)。水下跑步机水的总细菌计数为1,600至2,800cfu/mL。在所有检测到的推定细菌物种中,SIM倾向于对狗更有致病性。在这些诊所中有针对性的清洁/消毒可以帮助降低使用这些诊所的动物和看护者的风险。
    The presence of potentially pathogenic bacteria on veterinary clinic surfaces may be problematic. In this study, we collected swab samples (Fisherbrand, double transport swabs with Stuart\'s liquid medium) and water samples from five veterinary rehabilitation clinics. Swabs and water samples were transported to a microbiology lab for processing. At the lab, swabs were used to inoculate Hardy\'s Cdiff Banana Broth (for Clostridium difficile [Cdiff]) and five different types of bacterial growth media, including Hardy CHROM MRSA agar (methicillin-resistant Staphylococcus aureus [MRSA] and S. pseudintermedius [SIM]), mannitol salt agar (S. aureus [SA]), eosin methylene blue agar (enterics [ENT]), Pseudomonas isolation agar (Pseudomonas spp. [PS]), and tryptic soy agar [TSA] (non-specific). The most prominent presumptive species cultured was Cdiff (on nearly 55% of swabs). Bacillus spp. and enteric bacteria were encountered on nearly 35% of swabs, with MRSA and SIM on just over 10% of swabs. The most contaminated sample site was harnesses/life jackets used with the underwater treadmill (33% of swabs). The underwater treadmill water had total bacterial counts from 1,600 to 2,800 cfu/mL. Of all presumptive bacterial species detected, SIM tends to be more pathogenic for dogs. Targeted cleaning/disinfecting in these clinics could help reduce risks for both animals and caregivers utilizing these clinics.
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  • 文章类型: Journal Article
    不断研究控制金黄色葡萄球菌和其他病原体的替代策略,有了Nisin,一种细菌素,在食品工业中广泛用作生物防腐剂,获得越来越多的关注。除了其抗菌性能,即使在抑制浓度下,细菌素也对基因组功能具有显着影响。本研究调查了亚抑制浓度的乳酸链球菌素对金黄色葡萄球菌的影响。在0.625μmoll-1乳酸链球菌素存在下培养,导致hla的相对表达增加,saeR,还有Sara,在表达海基因时与毒力相关的基因,编码葡萄球菌肠毒素A(SEA),decreased.在体内实验中,感染后72小时,接种了在乳酸链球菌素存在下培养的金黄色葡萄球菌的海棠幼虫的死亡率为97%,相比之下,感染金黄色葡萄球菌的幼虫死亡率超过40%。全面了解乳链菌肽对毒力基因转录反应的影响以及这些变化对金黄色葡萄球菌毒力的影响,有助于评估这种细菌素在食品和医疗环境中的应用。
    Alternative strategies for controlling Staphylococcus aureus and other pathogens have been continuously investigated, with nisin, a bacteriocin widely used in the food industry as a biopreservative, gaining increasing attention. In addition to its antimicrobial properties, bacteriocins have significant effects on genome functionality even at inhibitory concentrations. This study investigated the impact of subinhibitory concentrations of nisin on S. aureus. Culturing in the presence of 0.625 μmol l-1 nisin, led to the increased relative expression of hla, saeR, and sarA, genes associated with virulence while expression of the sea gene, encoding staphylococcal enterotoxin A (SEA), decreased. In an in vivo experiment, Galleria mellonella larvae inoculated with S. aureus cultured in the presence of nisin exhibited 97% mortality at 72 h post-infection, compared to over 40% of larvae mortality in larvae infected with S. aureus. A comprehensive understanding of the effect of nisin on the transcriptional response of virulence genes and the impact of these changes on the virulence of S. aureus can contribute to assessing the application of this bacteriocin in food and medical contexts.
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  • 文章类型: Journal Article
    背景:假中间葡萄球菌和金黄色葡萄球菌是狗的重要病原体。这项研究建立了承运人费率,坦桑尼亚健康犬中这些细菌的菌株多样性和耐药性。
    结果:基于口腔和会阴拭子的培养,151只健康犬中,有11.3%和50.3%是金黄色葡萄球菌和假中介葡萄球菌的携带者,分别。只有四只狗(3%)携带耐甲氧西林金黄色葡萄球菌(MRSA),而假中介链球菌菌株均无耐甲氧西林。19株金黄色葡萄球菌中12株对青霉素G,对恩诺沙星和四环素的耐药性也很常见。所测试的103个假中介链球菌菌株中最常见的耐药性是青霉素G(28.2%)和四环素(22.3%)。假中间菌株显示65种不同的随机扩增多态性DNA(RAPD)指纹图谱,金黄色葡萄球菌菌株属于八种不同的spa类型,包括两个新颖的类型(t18988和t18989)。MRSA菌株携带SCCmecV型。
    结论:坦桑尼亚的健康狗是低频率的MRSA携带者,一半的狗携带具有高品系多样性的假中间杆菌。
    BACKGROUND: Staphylococcus pseudintermedius and S. aureus are important pathogens in dogs. This study established carrier rates, strain diversity and antimicrobial resistance of these bacteria among healthy dogs in Tanzania.
    RESULTS: Based on cultures of mouth and perineal swabs, 11.3% and 50.3% of 151 healthy dogs were carriers of S. aureus and S. pseudintermedius, respectively. Only four dogs (3%) carried meticillin-resistant S. aureus (MRSA), while none of the S. pseudintermedius strains were meticillin-resistant. 12 of 19 S. aureus strains tested were resistant to penicillin G, and resistance to enrofloxacin and tetracycline was also commonly detected. The most common resistances in 103 S. pseudintermedius strains tested were to penicillin G (28.2%) and tetracycline (22.3%). S. pseudintermedius strains showed 65 different random amplified polymorphic DNA (RAPD) fingerprints, and S. aureus strains belonged to eight different spa types, including two novel types (t18988 and t18989). MRSA strains carried SCCmec type V.
    CONCLUSIONS: Healthy dogs in Tanzania were carriers of MRSA at low frequency, and half of the dogs carried S. pseudintermedius with high strain diversity.
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  • 文章类型: Journal Article
    抗生素耐药性(ABR)危机是一个紧迫的全球卫生优先事项。葡萄球菌是导致这种紧急情况的有问题的细菌之一,因为它们对许多临床上重要的抗生素不兼容。小集落变异(SCV)的存在进一步使葡萄球菌发病机制复杂化。表现出非典型特征的细菌亚群,包括生长迟缓,多产的生物膜形成,提高抗生素耐受性,增强了细胞内的持久性。这些能力严重阻碍了目前的化疗药物,导致慢性感染,患者预后差,和巨大的经济负担。解决ABR需要替代措施,而不是在过去的80年中主导治疗方案的传统选择。非抗生素疗法在这个领域越来越受到人们的关注,包括蜂蜜的使用,尽管有古老的治疗根源,现在已经被重新想象为传统局部使用之外的替代疗法,包括一系列难以治疗的葡萄球菌感染的治疗。本文综述了麦卢卡蜂蜜(MH)及其作为抗葡萄球菌治疗的功效。我们总结了使用该产品的研究以及用于研究抗菌机制的技术,这些抗菌机制使MH成为管理有问题的葡萄球菌感染的合适药物,包括涉及葡萄球菌SCV的那些。我们还讨论了葡萄球菌对MH的耐药性发展状况以及可能影响其作为替代治疗以帮助对抗ABR的疗效的其他因素。
    The antibiotic resistance (ABR) crisis is an urgent global health priority. Staphylococci are among the problematic bacteria contributing to this emergency owing to their recalcitrance to many clinically important antibiotics. Staphylococcal pathogenesis is further complicated by the presence of small colony variants (SCVs), a bacterial subpopulation displaying atypical characteristics including retarded growth, prolific biofilm formation, heightened antibiotic tolerance, and enhanced intracellular persistence. These capabilities severely impede current chemotherapeutics, resulting in chronic infections, poor patient outcomes, and significant economic burden. Tackling ABR requires alternative measures beyond the conventional options that have dominated treatment regimens over the past 8 decades. Non-antibiotic therapies are gaining interest in this arena, including the use of honey, which despite having ancient therapeutic roots has now been reimagined as an alternative treatment beyond just traditional topical use, to include the treatment of an array of difficult-to-treat staphylococcal infections. This literature review focused on Manuka honey (MH) and its efficacy as an anti-staphylococcal treatment. We summarized the studies that have used this product and the technologies employed to study the antibacterial mechanisms that render MH a suitable agent for the management of problematic staphylococcal infections, including those involving staphylococcal SCVs. We also discussed the status of staphylococcal resistance development to MH and other factors that may impact its efficacy as an alternative therapy to help combat ABR.
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  • 文章类型: Journal Article
    背景:尽管对人类护理下的动物的整体状况至关重要,关于新热带灵长类动物口腔健康的信息仍然有限。
    方法:我们在人类护理下使用质谱分析了13只卷尾猴(Sapajusapella)的主要口腔条件和微生物群。根据Triadan系统,这些发现记录在牙列图上。
    结果:最普遍的情况是牙齿骨折(n=9),主要是牙釉质骨折,和牙周病(n=8),主要是一年级的结石。当驱逐牙齿时,在416个评估的作品中,有90个发现了改变,是最常见的牙周病(n=60),其次是牙釉质骨折(n=15)和牙齿缺失(n=10)。在口腔微生物群分析中,葡萄球菌和链球菌是最普遍的,尽管在分离的生物和口腔条件之间没有观察到明显的关联。
    结论:这些发现具有预防口腔疾病的潜力,包括骨折和牙周病,有助于口腔微生物群的分子鉴定,并在人类护理下改善灵长类动物的福祉。
    BACKGROUND: Although critical to the overall condition of animals under human care, there is still limited information about oral health in neotropical primates.
    METHODS: We analyzed the main oral conditions and microbiota using mass spectrometry from 13 capuchin monkeys (Sapajus apella) under human care. The findings were registered on odontograms following the Triadan system.
    RESULTS: The most prevalent conditions were dental fractures (n = 9), mainly enamel fractures, and periodontal disease (n = 8), mainly grade 1 calculi. When exanimating teeth, alterations were identified in 90 out of the 416 evaluated pieces, being periodontal disease the most common (n = 60), followed by enamel fracture (n = 15) and missing teeth (n = 10). In the oral microbiota analyses, Staphylococcus and Streptococcus species were the most prevalent, although no obvious association was observed between isolated organisms and oral conditions.
    CONCLUSIONS: These findings hold the potential to prevent oral disorders, including fractures and periodontal diseases, contribute to molecular identification of oral microbiota, and to improve the well-being of primates under human care.
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  • 文章类型: Journal Article
    关于葡萄球菌属的发生的已发表研究很少。在南非的狗中。该研究的目的是表征葡萄球菌属物种。从提交给南非兽医诊断实验室的狗样本中分离出的时间,地点,和人。这项研究利用了2012年至2017年从南非兽医诊断实验室获得的1627个阳性葡萄球菌分离株的数据集。在1627年确认的分离株中,鉴定出10种不同的葡萄球菌。其中,92.0%被归类为凝固酶阳性葡萄球菌(CoPS),6.0%为凝固酶阴性葡萄球菌(CoNS),3.0%为凝固酶变量。雄性狗占葡萄球菌分离株的一半以上(53.2%),而雌性狗贡献了其余的46.8%。最大比例的分离株(23.2%)来自年龄≥9岁的狗,来自夸祖鲁-纳塔尔省的分离株最多(45.0%),来自北开普省的分离株最少(0.1%)。在记录中包含的总样本中,大部分(46.0%)为皮肤标本。记录的葡萄球菌分离株数量在季节之间变化有限(秋季为24.3%,冬季26.3%,春季为26.0%,夏季为24.0%)。这项研究强调了葡萄球菌的多样性。与狗隔离,以及南非狗中葡萄球菌运输的负担。需要进一步的研究来检查导致观察到的葡萄球菌比例差异的因素。各省之间。
    There is a scarcity of published studies on the occurrence of Staphylococcus spp. Among dogs in South Africa. The objective of the study was to characterise the Staphylococcus spp. Isolated from dog samples submitted to a veterinary diagnostic laboratory in South Africa in terms of time, place, and person. This study utilised a dataset of 1627 positive Staphylococcus isolates obtained from a veterinary diagnostic laboratory in South Africa from 2012 to 2017. Out of the 1627 confirmed isolates, 10 different species of Staphylococcus were identified. Among these, 92.0% were classified as coagulase-positive staphylococci (CoPS), 6.0% were coagulase-negative staphylococci (CoNS), and 3.0% were coagulase-variable. Male dogs contributed just over half (53.2%) of the Staphylococcus isolates, while female dogs contributed the remaining 46.8%. The largest proportion of isolates (23.2%) were obtained from dogs aged ≥ 9 years, with the highest number of isolates originating from KwaZulu-Natal Province (45.0%) and the least from Northern Cape Province (0.1%). Out of the total samples included in the records, the majority (46.0%) were skin specimens. The number of Staphylococcus isolates recorded showed limited variation between the seasons (24.3% in autumn, 26.3% in winter, 26.0% in spring, and 24.0% in summer). This study highlighted the diversity of Staphylococcus spp. isolated from dogs, and the burden of staphylococcal carriage among dogs in South Africa. Further research is required to examine the factors that contribute to the observed discrepancies in the proportions of Staphylococcus spp. between the provinces.
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  • 文章类型: Journal Article
    表皮葡萄球菌,在人类皮肤上发现的一种常见共生细菌,会在临床环境中引起感染,抗生素抗性基因(ARGs)的存在阻碍了表皮葡萄球菌感染的治疗。然而,在基因组和生态多样性方面表征表皮葡萄球菌中ARGs的研究有限。因此,我们对405个高质量的表皮葡萄球菌基因组进行了全面和比较分析,包括汉江的35个环境分离物,研究该病原体中抗生素抗性的基因组多样性。比较基因组分析揭示了与多位点序列类型相关的表皮葡萄球菌基因组中ARG的流行。编码二氢叶酸还原酶(dfrC)和多药外排泵(norA)的基因是全基因组核心ARGs。β-内酰胺类ARGs在表皮葡萄球菌基因组中也非常普遍,这与在河流分离株中观察到的抗性表型一致。此外,我们在六个河流分离株的质粒样序列中鉴定了氯霉素乙酰转移酶基因(cat),以前在表皮葡萄球菌基因组中没有报道过。这些基因与屎肠球菌质粒所携带的基因相同,并与插入序列6家族转座酶相关,与在金黄色葡萄球菌质粒中发现的那些同源,提示这些革兰氏阳性病原体之间水平基因转移的可能性。表皮葡萄球菌和金黄色葡萄球菌基因组之间的ARG和毒力因子谱的比较表明,这两个物种是明确区分的,尽管存在生态重叠,但仍表明基因组划界。我们的发现为表皮葡萄球菌抗生素抗性的基因组多样性提供了全面的理解。
    目的:需要从基因组的角度全面了解皮肤共生菌和条件致病菌表皮葡萄球菌的抗生素耐药基因(ARG)谱。我们的研究包括对来自不同栖息地的整个表皮葡萄球菌基因组的比较分析,包括本研究中测序的汉江环境分离株。我们的结果揭示了不同表皮葡萄球菌多基因座序列类型中ARGs的分布和多样性,为与抗生素抗性相关的生态和遗传因素提供有价值的见解。表皮葡萄球菌和金黄色葡萄球菌之间的比较揭示了ARG和毒力因子谱的显着差异,尽管它们的生态位重叠。
    Staphylococcus epidermidis, a common commensal bacterium found on human skin, can cause infections in clinical settings, and the presence of antibiotic resistance genes (ARGs) impedes the treatment of S. epidermidis infections. However, studies characterizing the ARGs in S. epidermidis with regard to genomic and ecological diversities are limited. Thus, we performed a comprehensive and comparative analysis of 405 high-quality S. epidermidis genomes, including those of 35 environmental isolates from the Han River, to investigate the genomic diversity of antibiotic resistance in this pathogen. Comparative genomic analysis revealed the prevalence of ARGs in S. epidermidis genomes associated with multi-locus sequence types. The genes encoding dihydrofolate reductase (dfrC) and multidrug efflux pump (norA) were genome-wide core ARGs. β-Lactam class ARGs were also highly prevalent in the S. epidermidis genomes, which was consistent with the resistance phenotype observed in river isolates. Furthermore, we identified chloramphenicol acetyltransferase genes (cat) in the plasmid-like sequences of the six river isolates, which have not been reported previously in S. epidermidis genomes. These genes were identical to those harbored by the Enterococcus faecium plasmids and associated with the insertion sequence 6 family transposases, homologous to those found in Staphylococcus aureus plasmids, suggesting the possibility of horizontal gene transfer between these Gram-positive pathogens. Comparison of the ARG and virulence factor profiles between S. epidermidis and S. aureus genomes revealed that these two species were clearly distinguished, suggesting genomic demarcation despite ecological overlap. Our findings provide a comprehensive understanding of the genomic diversity of antibiotic resistance in S. epidermidis.
    OBJECTIVE: A comprehensive understanding of the antibiotic resistance gene (ARG) profiles of the skin commensal bacterium and opportunistic pathogen Staphylococcus epidermidis needs to be documented from a genomic point of view. Our study encompasses a comparative analysis of entire S. epidermidis genomes from various habitats, including those of 35 environmental isolates from the Han River sequenced in this study. Our results shed light on the distribution and diversity of ARGs within different S. epidermidis multi-locus sequence types, providing valuable insights into the ecological and genetic factors associated with antibiotic resistance. A comparison between S. epidermidis and Staphylococcus aureus revealed marked differences in ARG and virulence factor profiles, despite their overlapping ecological niches.
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  • 文章类型: Journal Article
    目的:本研究旨在确定摩洛哥卡萨布兰卡地区发生葡萄球菌尿路感染(UTI)的患病率和危险因素。
    方法:在卡萨布兰卡,摩洛哥,在2020年1月至2022年12月期间,对772例UTIs患者进行了回顾性评估.该研究包括两组患者:患有葡萄球菌UTI的患者和没有葡萄球菌UTI的患者。性,年龄,慢性疾病,抗生素暴露,导尿术,泌尿外科手术,和UTIs病史是评估的风险变量。我们采用逻辑回归模型来确定葡萄球菌UTI的预测特征。
    结果:在772个非重复个体中,8种葡萄球菌导致16.84%的UTI。感染腐生链球菌的患者(35.38%)是最常见的,其次是感染表皮葡萄球菌(24.61%),金黄色葡萄球菌(13.85%),和溶血链球菌(10.78%)。多因素logistic回归分析显示男性(95%CI:0.261-0.563),免疫抑制和免疫抑制治疗(95%CI:0.0068-0.64),慢性病(95%CI:0.407-0.965),以前的UTI(95%CI:0.031-0.228),每天排尿次数超过8次(95%CI:1.04-3.29),每天一次或两次排尿频率(95%CI:1.05-2.39),和导尿(95%CI:0.02-0.22)是葡萄球菌UTI的最可能预测因子。此外,较大比例的葡萄球菌UTIs患者了解与葡萄球菌UTIs相关的危险因素(52.31%,χ2=4.82,=0.014)。
    结论:这是第一个评估葡萄球菌引起的尿路感染的预测因素的全球研究。监测这些因素将使医疗机构能够制定有效的策略来管理尿路感染和对抗抗生素耐药性。
    OBJECTIVE: This study aimed to ascertain the prevalence and risk factors for developing staphylococcal urinary tract infections (UTIs) in the Casablanca area of Morocco.
    METHODS: In Casablanca, Morocco, a retrospective evaluation of 772 UTIs patients was conducted between January 2020 and December 2022. The research included two groups of patients: those with staphylococcal UTIs and those without. Sex, age, chronic illnesses, antibiotic exposure, urinary catheterization, urological surgery, and UTIs history were the risk variables assessed. We employed a logistic regression model to identify the characteristics that were predictive of staphylococcal UTIs.
    RESULTS: Eight staphylococcal species were responsible for 16.84% of UTIs in 772 non-repeating individuals. Patients infected with S. saprophyticus (35.38%) were the most common, followed by those infected with S. epidermidis (24.61%), S. aureus (13.85%), and S. hemolyticus (10.78%). Multivariate logistic regression analysis revealed that male sex (95% CI: 0.261-0.563), immunosuppression and immunosuppressive treatments (95% CI: 0.0068-0.64), chronic diseases (95% CI: 0.407-0.965), previous UTIs (95% CI: 0.031-0.228), frequency of urination more than 8 times a day (95% CI:1.04-3.29), frequency of urination once or twice a day (95% CI: 1.05-2.39), and urinary catheterization (95% CI: 0.02-0.22) were the most likely predictors of staphylococcal UTIs. In addition, a larger proportion of patients with staphylococcal UTIs were made aware of the risk factors associated with staphylococcal UTIs (52.31%, χ2 = 4.82, = 0.014).
    CONCLUSIONS: This is the first global study to evaluate the predictive factors for acquiring UTIs caused by staphylococci. Monitoring these factors will enable medical authorities to devise effective strategies for managing UTIs and combating antibiotic resistance.
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  • 文章类型: Journal Article
    目的:本研究旨在开发一种可编辑的结构支架,用于通过使用衍生自(杂)芳基-喹啉混合支架的合成化合物来改善药物开发,包括抗生素的药代动力学和药效学。
    结果:在这项研究中,通过测定最小抑制浓度,检查18个CF3-取代的(杂)芳基-喹啉杂合分子对金黄色葡萄球菌的潜在抗菌活性。这18种合成化合物代表了喹啉N-氧化物支架关键区域的修饰,使我们能够进行结构-活性关系(SAR)分析抗菌效力。在这些化合物中,3m表现出对两种耐甲氧西林金黄色葡萄球菌(MRSA)菌株的效力,以及其他革兰氏阳性菌,包括粪肠球菌和枯草芽孢杆菌。通过监测PMF并进行分子动力学模拟,我们证明了3m破坏了细菌质子动力(PMF)。此外,我们证明了这种作用机制,破坏PMF,对金黄色葡萄球菌来说是具有挑战性的。我们还在具有减弱的脂多糖(LPS)的鲍曼不动杆菌菌株中验证了3m的这种PMF抑制机制。此外,在革兰氏阴性细菌中,我们证明3m与粘菌素具有协同作用,破坏革兰氏阴性细菌的外膜。
    结论:我们开发可编辑的合成新型抗菌药物的方法强调了CF3取代的(杂)芳基喹啉支架用于设计靶向细菌质子动力的化合物的实用性,为了进一步的药物开发,包括药代动力学和药效学。
    OBJECTIVE: This study aimed to develop an editable structural scaffold for improving drug development, including pharmacokinetics and pharmacodynamics of antibiotics by using synthetic compounds derived from a (hetero)aryl-quinoline hybrid scaffold.
    RESULTS: In this study, 18 CF3-substituted (hetero)aryl-quinoline hybrid molecules were examined for their potential antibacterial activity against Staphylococcus aureus by determining minimal inhibitory concentrations. These 18 synthetic compounds represent modifications to key regions of the quinoline N-oxide scaffold, enabling us to conduct a structure-activity relationship analysis for antibacterial potency. Among the compounds, 3 m exhibited potency against with both methicillin resistant S. aureus strains, as well as other Gram-positive bacteria, including Enterococcus faecalis and Bacillus subtilis. We demonstrated that 3 m disrupted the bacterial proton motive force (PMF) through monitoring the PMF and conducting the molecular dynamics simulations. Furthermore, we show that this mechanism of action, disrupting PMF, is challenging for S. aureus to overcome. We also validated this PMF inhibition mechanism of 3 m in an Acinetobacter baumannii strain with weaken lipopolysaccharides. Additionally, in Gram-negative bacteria, we demonstrated that 3 m exhibited a synergistic effect with colistin that disrupts the outer membrane of Gram-negative bacteria.
    CONCLUSIONS: Our approach to developing editable synthetic novel antibacterials underscores the utility of CF3-substituted (hetero)aryl-quinoline scaffold for designing compounds targeting the bacterial proton motive force, and for further drug development, including pharmacokinetics and pharmacodynamics.
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