scholarly journals Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 873
Author(s):  
Wern Chern Chai ◽  
Jonathan J. Whittall ◽  
Di Song ◽  
Steven W. Polyak ◽  
Abiodun D. Ogunniyi ◽  
...  
Keyword(s):  
Cell Division ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Coli Strain ◽  
Haemolytic Activity ◽  
Bacterial Cell Division ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics ◽  
Mrsa Strains ◽  
Ftsz Inhibitors

The bacterial cell division protein, FtsZ, has been identified as a target for antimicrobial development. Derivatives of 3-methoxybenzamide have shown promising activities as FtsZ inhibitors in Gram-positive bacteria. We sought to characterise the activity of five difluorobenzamide derivatives with non-heterocyclic substituents attached through the 3-oxygen. These compounds exhibited antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA), with an isopentyloxy-substituted compound showing modest activity against vancomycin resistant Enterococcus faecium (VRE). The compounds were able to reverse resistance to oxacillin in highly resistant clinical MRSA strains at concentrations far below their MICs. Three of the compounds inhibited an Escherichia coli strain lacking the AcrAB components of a drug efflux pump, which suggests the lack of Gram-negative activity can partly be attributed to efflux. The compounds inhibited cell division by targeting S. aureus FtsZ, producing a dose-dependent increase in GTPase rate which increased the rate of FtsZ polymerization and stabilized the FtsZ polymers. These compounds did not affect the polymerization of mammalian tubulin and did not display haemolytic activity or cytotoxicity. These derivatives are therefore promising compounds for further development as antimicrobial agents or as resistance breakers to re-sensitive MRSA to beta-lactam antibiotics.

scholarly journals Mechanisms of Resistance to Quinolones and Epidemiological Significance of Salmonella spp.

2016 ◽  
Vol 66 (2) ◽  
pp. 147-159 ◽  
Author(s):  
Maja Velhner
Keyword(s):  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Resistance Mechanism ◽  
Quinolone Resistance ◽  
Beta Lactam ◽  
Foodborne Illnesses ◽  
Salmonella Spp ◽  
Over Expression ◽  
Beta Lactam Antibiotics ◽  
Chromosomal Mutations

Abstract Bacteria develop resistance to antimicrobial agents by a number of different mechanisms. The resistance to (fluoro)quinolones in Salmonella is of particular importance especially if therapy in humans is required. For decades there has been a significant interest in studying the biology of Salmonella because these bacteria are among the leading causes of foodborne illnesses around the globe. To this date, two main mechanisms of quinolone resistance have been established: alteration in the targets for quinolones, decreased accumulation inside bacteria due to impermeability of the membrane and/or an over expression of the efflux pump systems. Both of these mechanisms are chromosomally mediated. Furthermore, mobile elements have been described carrying the qnr gene which confers resistance to quinolones. The plasmid encoded QNR proteins belong to the pentapeptide repeat family of proteins. The plasmid mediated quinolone resistance (PMQR) is often associated with the resistance to beta lactam antibiotics. It was noticed that PMQR is backing up chromosomal mutations for quinolone resistance, hence becoming an important resistance mechanism worldwide. Even with our knowledge expanding over the years, it is not possible to predict how bacteria will respond in the future, if they are exposed to new external challenges. The possibility that they will find a way to survive by introducing new mutations or by exchanging mobile genetic elements and subsequently developing resistance to survive in the environment should not be underestimated.

Discovery of FtsZ inhibitors by virtual screening as antibacterial agents and study of the inhibition mechanism

2021 ◽  
Author(s):  
Ruo-Lan Du ◽  
Ning Sun ◽  
Yik-Hong Fung ◽  
Yuanyuan Zheng ◽  
Yu Wai Chen ◽  
...  
Keyword(s):  
Cell Division ◽  
Virtual Screening ◽  
Bacterial Cell ◽  
Drug Target ◽  
Antibacterial Agents ◽  
Antimicrobial Agents ◽  
Inhibition Mechanism ◽  
Bacterial Cell Division ◽  
Ftsz Protein ◽  
Ftsz Inhibitors

Inhibition of bacterial cell division is a novel mechanistic action in the development of new antimicrobial agents. The FtsZ protein is an important antimicrobial drug target because of its essential...

scholarly journals Benzamide Derivatives Targeting the Cell Division Protein FtsZ: Modifications of the Linker and the Benzodioxane Scaffold and Their Effects on Antimicrobial Activity

Antibiotics ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 160 ◽  
Author(s):  
Valentina Straniero ◽  
Lorenzo Suigo ◽  
Andrea Casiraghi ◽  
Victor Sebastián-Pérez ◽  
Martina Hrast ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Cell Division ◽  
Single Molecule ◽  
Efflux Pump ◽  
Computational Study ◽  
Structural Features ◽  
Temperature Sensitive ◽  
Bacterial Cell Division ◽  
Gram Positive ◽  
Prokaryotic Protein

Filamentous temperature-sensitive Z (FtsZ) is a prokaryotic protein with an essential role in the bacterial cell division process. It is widely conserved and expressed in both Gram-positive and Gram-negative strains. In the last decade, several research groups have pointed out molecules able to target FtsZ in Staphylococcus aureus, Bacillus subtilis and other Gram-positive strains, with sub-micromolar Minimum Inhibitory Concentrations (MICs). Conversely, no promising derivatives active on Gram-negatives have been found up to now. Here, we report our results on a class of benzamide compounds, which showed comparable inhibitory activities on both S. aureus and Escherichia coli FtsZ, even though they proved to be substrates of E. coli efflux pump AcrAB, thus affecting the antimicrobial activity. These surprising results confirmed how a single molecule can target both species while maintaining potent antimicrobial activity. A further computational study helped us decipher the structural features necessary for broad spectrum activity and assess the drug-like profile and the on-target activity of this family of compounds.

scholarly journals DRUG UTILIZATION STUDY IN THE ORTHOPEDICS OUTPATIENT DEPARTMENT OF A TERTIARY CARE HOSPITAL IN MAHARASHTRA

2018 ◽  
Vol 11 (9) ◽  
pp. 224
Author(s):  
Madhuri Kulkarni ◽  
Anant Patil
Keyword(s):  
Retrospective Study ◽  
Drug Utilization ◽  
Antimicrobial Agents ◽  
Tertiary Care Hospital ◽  
Tertiary Care ◽  
Care Hospital ◽  
Beta Lactam ◽  
Drug Utilization Study ◽  
Beta Lactam Antibiotics ◽  
Prescribed Medicines

Objective: The objective of this study was to analyze the pattern of drug utilization in outpatients of orthopedics department from a tertiary care hospital.Material and Methods: In this retrospective study, prescriptions of randomly selected patients attending orthopedics clinic were screened to analyze a number of medicines per prescription. Number and percentages of prescribed medicines were calculated.Results: In this study, 512 patients (male 260 [50.8%] and females 252 [49.2%]) were included in the study. The total number of prescribed medicines was 1562, accounting for 3.1 medicines per patient. A total number of oral, parenteral, and topical medicines were 1375 (88%), 176 (11.3%), and 11 (0.7%), respectively. Nonsteroidal anti-inflammatory agents (NSAIDs), antacid/anti-ulcerants, and antimicrobial agents were 641 (41%), 371 (23.8%), and 102 (6.5%), respectively. A total of 54 (52.9%), 29 (28.4%), 9 (8.8%), 6 (5.9%), 3 (2.9%), and 1 (1%) patients were prescribed fluoroquinolones, beta-lactam antibiotics, metronidazole, trimethoprim plus sulfamethoxazole, macrolides, and doxycycline, respectively. For 371 (23.8%) patients, anti-ulcerant and antiulcer were prescribed, among which ranitidine was the most common prescription [353 (95.1%)]Conclusion: Number of medicines prescribed per patient in orthopedic clinic was 3.1. NSAIDs and antacid/anti-ulcerants were the most commonly prescribed medicines.

Motile Aeromonas as agent of infections of the foot

1995 ◽  
Vol 85 (9) ◽  
pp. 505-508 ◽  
Author(s):  
M Wakabongo
Keyword(s):  
Second Generation ◽  
Antimicrobial Agents ◽  
Third Generation ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics ◽  
Taxonomic Uncertainty ◽  
Post Traumatic ◽  
Third Generation Cephalosporins

Motile Aeromonas infections of the foot are caused mostly by post-traumatic incidence, occurring mostly during summer months. Serious complications such as osteomyelitis and amputation can result if the infections go untreated or are inadequately treated. The role of each species of motile Aeromonas in pathogenesis and response to antimicrobial agents is not well understood because of taxonomic uncertainty. As a group, motile Aeromonas respond well to aminoglycosides, second-generation and third-generation cephalosporins, quinolones, and some beta-lactam antibiotics.

scholarly journals Full-Genome Sequencing Identifies in the Genetic Background Several Determinants That Modulate the Resistance Phenotype in Methicillin-Resistant Staphylococcus aureus Strains Carrying the Novel mecC Gene

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Catarina Milheiriço ◽  
Hermínia de Lencastre ◽  
Alexander Tomasz
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Genetic Background ◽  
Beta Lactam ◽  
Methicillin Resistant ◽  
Content Type ◽  
Resistance Phenotype ◽  
Beta Lactam Antibiotics ◽  
Oxacillin Resistance ◽  
Mrsa Strains

ABSTRACT Most methicillin-resistant Staphylococcus aureus (MRSA) strains are resistant to beta-lactam antibiotics due to the presence of the mecA gene, encoding an extra penicillin-binding protein (PBP2A) that has low affinity for virtually all beta-lactam antibiotics. Recently, a new resistance determinant—the mecC gene—was identified in S. aureus isolates recovered from humans and dairy cattle. Although having typically low MICs to beta-lactam antibiotics, MRSA strains with the mecC determinant are also capable of expressing high levels of oxacillin resistance when in an optimal genetic background. In order to test the impact of extensive beta-lactam selection on the emergence of mecC-carrying strains with high levels of antibiotic resistance, we exposed the prototype mecC-carrying MRSA strain, LGA251, to increasing concentrations of oxacillin. LGA251 was able to rapidly adapt to high concentrations of oxacillin in growth medium. In such laboratory mutants with increased levels of oxacillin resistance, we identified mutations in genes with no relationship to the mecC regulatory system, indicating that the genetic background plays an important role in the establishment of the levels of oxacillin resistance. Our data also indicate that the stringent stress response plays a critical role in the beta-lactam antibiotic resistance phenotype of MRSA strains carrying the mecC determinant.

scholarly journals Prevalence of Plasmid-Mediated Quinolone Resistance Determinants and OqxAB Efflux Pumps among Extended-Spectrumβ-Lactamase ProducingKlebsiella pneumoniaeIsolated from Patients with Nosocomial Urinary Tract Infection in Tehran, Iran

Scientifica ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Mehdi Goudarzi ◽  
Mehdi Azad ◽  
Sima Sadat Seyedjavadi
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Antimicrobial Agents ◽  
Quinolone Resistance ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics ◽  
Nosocomial Urinary Tract Infection ◽  
Clinical Resistance ◽  
Synergy Test

Objective. Plasmid-mediated quinolone resistance (PMQR) plays an important role in the development of clinical resistance to quinolone. The aim of this study was to investigate PMQR determinants among extended-spectrumβ-lactamases- (ESBL-) producingKlebsiella pneumoniaerecovered from patients with nosocomial urinary tract infection (UTI).Methods. A total of 247 ESBL-producingK. pneumoniaeisolates were collected from 750 patients with UTI. ESBL production was confirmed by double disc synergy test and combined disc diffusion test. The prevalence of PMQR determinants among ESBL-producingK. pneumoniaewas assessed using PCR method.Results. The rates of resistance to antimicrobial agents in present study varied from 14.2% to 98.8%. In comparison with other PMQR genotypes, the frequency ofaac(6′)-Ib(68.8%) was strikingly high. Of the 247 isolates tested,qnrA, qnrB, qnrS,andqepAgenes were present in 3.6%, 1.6%, 1.2, and 2%, respectively.oqxAandoqxBwere detected in 56.7% and 54.6% of isolates. The predominant coexisting ESBL and PMQR profile among our isolates includedblaCTX-Mandaac(6′)-Ib, oqxA, oqxB(28.3%) andblaTEM,blaSHVandaac(6′)-Ib, oqxA,andoqxB(19.4%) profile.  Conclusion. Given the linkage observed between resistance to quinolones and beta lactam antibiotics, therapeutic protocol with fluoroquinolones and beta lactam antibiotics should be seriously revised in Tehran hospitals.

scholarly journals Frequency and antimicrobial resistance of bacteria isolated from oral and topical medicaments from Hilla, Iraq

2012 ◽  
Vol 6 (06) ◽  
pp. 489-494 ◽  
Author(s):  
Alaa Hani Al-Charrakh
Keyword(s):  
High Resistance ◽  
Antimicrobial Agents ◽  
Pharmaceutical Products ◽  
High Rate ◽  
Diffusion Method ◽  
Bacterial Isolates ◽  
Beta Lactam ◽  
Disk Diffusion Method ◽  
Gram Negative ◽  
Beta Lactam Antibiotics

Introduction: The presence of microorganisms in pharmaceuticals is undesirable because they may cause spoilage of the product and may present an infection hazard to the consumers or patients.  Methodology: A total of 102 samples of oral and topical non-sterile pharmaceutical products were collected at random from different drug houses and pharmacies in Iraq, to investigate the microbial contamination of these products. Bacterial isolates recovered from these medicaments were subjected to susceptibility testing against various antibiotics by disk diffusion method according to Clinical and Laboratory Standards (CLSI) guidelines. Results: The results revealed that the occurrence of Gram-positive bacteria was in oral and topical medicaments while Gram-negative bacteria were only detected in topical medicaments. More than 58% of Bacillus isolates were resistant to lincomycin and Bacillus mycoides isolates were resistant to beta-lactam antibiotics and trimethoprim-sulfamethoxazole. Staphylococcus spp. showed a relatively high resistance to ampicillin, amoxicillin, penicillin, tetracycline, and trimethoprim-sulfamethoxazole. S. epidermidis had the highest number of multi-resistant isolates. Furthermore, 87.5% of isolated Gram-negative rods showed high resistance to beta-lactam antibiotics and 75% of them were highly resistant to erythromycin. One isolate of Pseudomonas aeruginosa was the most resistant among all Gram-negative rod isolates. Conclusion: The high rate of resistance to antimicrobial agents of bacterial isolates recovered from oral and topical medicaments in this study may indicate a widespread antibiotic resistance among bacteria isolated from different sources, including those of anthropological and environmental origin. 

Genomic Overview into the Evolving Epidemiology of Methicillin-Resistant Staphylococcus aureus

2020 ◽  
Vol 21 (3) ◽  
pp. 125-131
Author(s):  
Yara El dessouky ◽  
Shaimaa Mouftah ◽  
Mohamed Elhadidy
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Human Infection ◽  
Emerging Infections ◽  
Beta Lactam ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Beta Lactam Antibiotics ◽  
Mrsa Strains ◽  
Hospital Acquired

Emerging infections represent an enormous challenge to both human and veterinary medicine. Identification of Methicillin-Resistant Staphylococcus aureus (MRSA) in various species and in food has raised concerns about the roles of animals in the epidemiology of MRSA. MRSA are a group of gram-positive bacteria, distinct from other strains of S. aureus in that this pathogen is resistant to methicillin, oxacillin, and all beta-lactam antibiotics. The severity of infections caused by MRSA depends on the strain responsible for the infection and can vary from soft tissue infections to bacteremia and sometimes pneumonia. MRSA strains are divided into clones, based on their genetic makeup. According to the setting of infection, MRSA are divided into three epidemiological types: hospital acquired (HA-MRSA), community acquired (CA-MRSA), and livestock acquired (LA-MRSA) (ie. Transmitted from animal carriers). The epidemiology of HA-MRSA, CA-MRSA, and LA-MRSA is blurred as different recent genetic studies have revealed significant overlap of identical clones between HA-MRSA and CA-MRSA, and the significant increase of human infection caused by LA-MRSA. Furthermore, the animal-human and animal-animal transmission of LA-MRSA has prompted further investigation to study the origin of this epidemiological type and the transmission dynamics. The genetic and virulence profiles of different types of MRSA vary widely, where community acquired and livestock acquired strains are more virulent than hospital acquired strains. This review sheds light on three epidemiological groups of MRSA (HA-MRSA, CA-MRSA, and LA-MRSA), and their most prevalent clonal clusters, that can consequently allow better understanding of their evolution, emergence, transmission, and global dissemination.

scholarly journals Rates of Carriage of Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus in an Outpatient Population

2003 ◽  
Vol 24 (6) ◽  
pp. 439-444 ◽  
Author(s):  
Julie Kenner ◽  
Tasha O'Connor ◽  
Nicholas Piantanida ◽  
Joel Fishbain ◽  
Bardwell Eberly ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Risk Factor ◽  
Clinical Risk Factor ◽  
Beta Lactam ◽  
Methicillin Resistant ◽  
Beta Lactam Antibiotics ◽  
Time Period ◽  
Clinical Illness ◽  
Mrsa Strains ◽  
Mrsa Colonization

AbstractObjectives:To assess the prevalence of and the clinical features associated with asymptomatic Staphylococcus aureus colonization in a healthy outpatient population, and to compare the characteristics of colonizing methicillin-resistant S. aureus (MRSA) strains with those of strains causing infection in our community and hospital.Setting:Outpatient military clinics.Methods:Specimens were obtained from the nares, pharynx, and axillae of 404 outpatients, and a questionnaire was administered to obtain demographic and risk factor information. MRSA strains were typed by pulsed-field gel electrophoresis (PFGE) and evaluated for antibiotic susceptibility. Antibiograms of study MRSA strains were compared with those of MRSA strains causing clinical illness during the same time period.Results:Methicillin-susceptible S. aureus (MSSA) colonization was present in 153 (38%) of the 404 asymptomatic outpatients, and MRSA colonization was present in 8 (2%). Detection of colonization was highest from the nares. No clinical risk factor was significantly associated with MRSA colonization; however, a tendency was noted for MRSA to be more common in men and in those who were older or who had been recently hospitalized. All colonizing MRSA strains had unique patterns on PFGE. In contrast to strains responsible for hospital infections, most colonizing isolates of MRSA were susceptible to oral antibiotics.Conclusions:MRSA and MSSA colonization is common in our outpatient population. Colonization is best detected by nares cultures and most carriers of MRSA are without apparent predisposing risk factors for acquisition. Colonizing isolates of MRSA are heterogeneous and, unlike nosocomial isolates, often retain susceptibility to other non-beta-lactam antibiotics.

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