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Scientific Reports Mar 2024Extended-spectrum beta-lactamase (ESBL)-producing organisms are widely recognized as clinically relevant causes of difficult-to-treat infections. CTX-M has formed a...
Extended-spectrum beta-lactamase (ESBL)-producing organisms are widely recognized as clinically relevant causes of difficult-to-treat infections. CTX-M has formed a rapidly growing family distributed worldwide among a wide range of clinical bacteria, particularly members of Enterobacteriaceae. Circulating banknotes, exchanged daily among people, pose a potential vehicle for transmitting multidrug resistance. We screened for ESBL-carrying bacteria in the present study and reported CTX-M mutations in Bangladesh's banknotes. We sequenced the genes and performed homology modeling using the Swiss model with CTX-M-15 (4HBT) as a template. Then, we performed molecular docking of mecillinam with the template and the generated model using Autodock 4.2 (Release 4.2.6). After docking, we visually inspected the complexes built using Autodock tools for polar contacts and pi-pi interactions in PyMOL 2.5.4. Our partially sequenced bla was related to bla and bla. We observed multiple single-nucleotide substitution mutations, i.e., G613T (silent mutation), A626T (I176F), and A503G (N135D). Homology modeling showed high similarity when the model was superimposed over the template. The orientation of Asn (135) in the template and Asp (135) in the model does not show a significant difference. Likewise, Ile (176) in the template and Phe (176) in the model offer the same orientation. Our generated model could bind to Lys237, Ser240, and Asp135 residues with the lowest binding energy on docking. Our predicted binding of the mecillinam to the mutated D-135 residue in the model indicates contributions and supports previous reports proposing CTX-M-15 to CTX-M-127 mutational conversion on the mecillinum resistance phenotype.
Topics: Humans; Molecular Docking Simulation; beta-Lactamases; Enterobacteriaceae; Amdinocillin; Mutation; Anti-Bacterial Agents; Escherichia coli Infections; Microbial Sensitivity Tests
PubMed: 38467683
DOI: 10.1038/s41598-024-56207-x -
Acta Obstetricia Et Gynecologica... Mar 2024Antibiotics are often prescribed during pregnancy. Assessing the current state of prenatal antibiotic use is therefore imperative for optimizing prescribing and...
INTRODUCTION
Antibiotics are often prescribed during pregnancy. Assessing the current state of prenatal antibiotic use is therefore imperative for optimizing prescribing and identifying emerging research priorities. The study aimed to describe recent trends and patterns in antibiotic use during pregnancy among women who gave birth in Sweden, including user characteristics.
MATERIAL AND METHODS
Population-based descriptive study using linked nationwide registers. All pregnancies delivered in Sweden from 2007 to 2019 were included. Prevalence of use was defined as the percentage of pregnancies during which at least one prescription forantibiotics was filled. Temporal trends in the prevalence of antibiotic use by calendar year, trimester and weeks of gestation were assessed from time series graphs.
RESULTS
Prescriptions for systemic antibiotics were filled in 20.7% of 1 434 431 pregnancies overall, decreasing from 24.7% in 2007 to 18.0% in 2019. Phenoxymethylpenicillin (8.5%), pivmecillinam (6.5%), nitrofurantoin (4.7%), amoxicillin (1.6%) and cefadroxil (1.5%) use were the most prevalent. Their use decreased over the 13-year period, except for pivmecillinam, which increased from 4.0% to 7.4%. Prevalence of use was highest in the second trimester (9.5%), with weekly trends peaking at 13 and 34 weeks of gestation. Compared with non-users, antibiotic users more often belonged to the youngest and oldest age strata, carried multipleton pregnancies, had delivered before, had attained a lower education level and smoked in early pregnancy. A higher body mass index, asthma, chronic renal disease and diabetes mellitus were more prevalent among antibiotic users than among non-users.
CONCLUSIONS
Although outpatient antibiotic use during pregnancy in Sweden has been declining, one in five pregnancies was exposed to systemic antibiotics.
Topics: Pregnancy; Female; Humans; Anti-Bacterial Agents; Amdinocillin Pivoxil; Sweden; Amoxicillin; Penicillin V
PubMed: 38108616
DOI: 10.1111/aogs.14741 -
Antimicrobial Agents and Chemotherapy May 2015Penicillin-binding proteins (PBPs) are integral players in bacterial cell division, and their catalytic activities can be monitored with β-lactam-containing chemical...
Penicillin-binding proteins (PBPs) are integral players in bacterial cell division, and their catalytic activities can be monitored with β-lactam-containing chemical probes. Compounds that target a single PBP could provide important information about the specific role(s) of each enzyme, making identification of such molecules important. We evaluated 22 commercially available β-lactams for inhibition of the PBPs in live Escherichia coli strain DC2. Whole cells were titrated with β-lactam antibiotics and subsequently incubated with a fluorescent penicillin derivative, Bocillin-FL (Boc-FL), to label uninhibited PBPs. Protein visualization was accomplished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) separation and fluorescent scanning. The examined β-lactams exhibited diverse PBP selectivities, with amdinocillin (mecillinam) showing selectivity for PBP2, aztreonam, piperacillin, cefuroxime, cefotaxime, and ceftriaxone for PBP3, and amoxicillin and cephalexin for PBP4. The remaining β-lactams did not block any PBPs in the DC2 strain of E. coli or inhibited more than one PBP at all examined concentrations in this Gram-negative organism.
Topics: Amdinocillin; Anti-Bacterial Agents; Aztreonam; Cefotaxime; Cefuroxime; Escherichia coli; Microbial Sensitivity Tests; Penicillin-Binding Proteins; beta-Lactams
PubMed: 25733506
DOI: 10.1128/AAC.04552-14 -
MBio Feb 2016The envelope of Gram-negative bacteria is an essential compartment that constitutes a protective and permeability barrier between the cell and its environment. The...
UNLABELLED
The envelope of Gram-negative bacteria is an essential compartment that constitutes a protective and permeability barrier between the cell and its environment. The envelope also hosts the cell wall, a mesh-like structure made of peptidoglycan (PG) that determines cell shape and provides osmotic protection. Since the PG must grow and divide in a cell-cycle-synchronized manner, its synthesis and remodeling are tightly regulated. Here, we discovered that PG homeostasis is intimately linked to the levels of activation of the Cpx system, an envelope stress response system traditionally viewed as being involved in protein quality control in the envelope. We first show that Cpx is activated when PG integrity is challenged and that this activation provides protection to cells exposed to antibiotics inhibiting PG synthesis. By rerouting the outer membrane lipoprotein NlpE, a known Cpx activator, to a different envelope subcompartment, we managed to manipulate Cpx activation levels. We found that Cpx overactivation leads to aberrant cellular morphologies, to an increased sensitivity to β-lactams, and to dramatic division and growth defects, consistent with a loss of PG homeostasis. Remarkably, these phenotypes were largely abrogated by the deletion of ldtD, a Cpx-induced gene involved in noncanonical PG cross-linkage, suggesting that this transpeptidase is an important link between PG homeostasis and the Cpx system. Altogether our data show that fine-tuning of an envelope quality control system constitutes an important layer of regulation of the highly organized cell wall structure.
IMPORTANCE
The envelope of Gram-negative bacteria is essential for viability. First, it includes the cell wall, a continuous polymer of peptidoglycan (PG) that determines cell morphology and protects against osmotic stress. Moreover, the envelope constitutes a protective barrier between the cell interior and the environment. Therefore, mechanisms called envelope stress response systems (ESRS) exist to monitor and defend envelope integrity against harmful conditions. Cpx is a major ESRS that detects and manages the accumulation of misfolded proteins in the envelope of Escherichia coli. We found that this protein quality control system also plays a fundamental role in the regulation of PG assembly. Strikingly, the level of Cpx response is critical, as an excessive activation leads to phenotypes associated with a loss of cell wall integrity. Thus, by contributing to PG homeostasis, the Cpx system lies at the crossroads between key processes of bacterial life, including cell shape, growth, division, and antibiotic resistance.
Topics: Amdinocillin; Bacterial Outer Membrane Proteins; Bacterial Proteins; Cell Wall; Cephalexin; Escherichia coli; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; Homeostasis; Lipoproteins; Membrane Proteins; Peptidoglycan; Phenotype; Protein Kinases; Stress, Physiological
PubMed: 26908573
DOI: 10.1128/mBio.00047-16 -
EBioMedicine Sep 2017
Topics: Amdinocillin; Escherichia coli; Humans; Microbial Sensitivity Tests
PubMed: 28864161
DOI: 10.1016/j.ebiom.2017.08.023 -
Nature Communications Oct 2016The peptidoglycan cell wall is an integral organelle critical for bacterial cell shape and stability. Proper cell wall construction requires the interaction of synthesis...
The peptidoglycan cell wall is an integral organelle critical for bacterial cell shape and stability. Proper cell wall construction requires the interaction of synthesis enzymes and the cytoskeleton, but it is unclear how the activities of individual proteins are coordinated to preserve the morphology and integrity of the cell wall during growth. To elucidate this coordination, we used single-molecule imaging to follow the behaviours of the two major peptidoglycan synthases in live, elongating Escherichia coli cells and after perturbation. We observed heterogeneous localization dynamics of penicillin-binding protein (PBP) 1A, the synthase predominantly associated with cell wall elongation, with individual PBP1A molecules distributed between mobile and immobile populations. Perturbations to PBP1A activity, either directly through antibiotics or indirectly through PBP1A's interaction with its lipoprotein activator or other synthases, shifted the fraction of mobile molecules. Our results suggest that multiple levels of regulation control the activity of enzymes to coordinate peptidoglycan synthesis.
Topics: Amdinocillin; Ampicillin; Anti-Bacterial Agents; Cefmetazole; Cefsulodin; Cell Wall; Diffusion; Escherichia coli; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; Penicillin-Binding Proteins; Peptidoglycan; Peptidoglycan Glycosyltransferase; Serine-Type D-Ala-D-Ala Carboxypeptidase; Single Molecule Imaging
PubMed: 27774981
DOI: 10.1038/ncomms13170 -
Antimicrobial Agents and Chemotherapy Jun 2017Zidebactam and WCK 5153 are novel β-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of the diazabicyclooctane (DBO) scaffold, targeted for the...
WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent "β-Lactam Enhancer" Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk Clones.
Zidebactam and WCK 5153 are novel β-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of the diazabicyclooctane (DBO) scaffold, targeted for the treatment of serious infections caused by highly drug-resistant Gram-negative pathogens. In this study, we determined the penicillin-binding protein (PBP) inhibition profiles and the antimicrobial activities of zidebactam and WCK 5153 against , including multidrug-resistant (MDR) metallo-β-lactamase (MBL)-producing high-risk clones. MIC determinations and time-kill assays were conducted for zidebactam, WCK 5153, and antipseudomonal β-lactams using wild-type PAO1, MexAB-OprM-hyperproducing (), porin-deficient (), and AmpC-hyperproducing () derivatives of PAO1, and MBL-expressing clinical strains ST175 () and ST111 (). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-2 (apparent [] > 100 μM). MICs for zidebactam and WCK 5153 ranged from 2 to 32 μg/ml (amdinocillin MICs > 32 μg/ml). Time-kill assays revealed bactericidal activity of zidebactam and WCK 5153. LIVE-DEAD staining further supported the bactericidal activity of both compounds, showing spheroplast formation. Fixed concentrations (4 or 8 μg/ml) of zidebactam and WCK 5153 restored susceptibility to all of the tested β-lactams for each of the mutant strains. Likewise, antipseudomonal β-lactams (CLSI breakpoints), in combination with 4 or 8 μg/ml of zidebactam or WCK 5153, resulted in enhanced killing. Certain combinations determined full bacterial eradication, even with MDR MBL-producing high-risk clones. β-Lactam-WCK enhancer combinations represent a promising β-lactam "enhancer-based" approach to treat MDR infections, bypassing the need for MBL inhibition.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Cyclooctanes; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Microbial Sensitivity Tests; Penicillin-Binding Proteins; Piperidines; Pseudomonas aeruginosa; beta-Lactamases; beta-Lactams
PubMed: 28289035
DOI: 10.1128/AAC.02529-16 -
Cell Dec 2014Penicillin and related beta-lactams comprise one of our oldest and most widely used antibiotic therapies. These drugs have long been known to target enzymes called...
Penicillin and related beta-lactams comprise one of our oldest and most widely used antibiotic therapies. These drugs have long been known to target enzymes called penicillin-binding proteins (PBPs) that build the bacterial cell wall. Investigating the downstream consequences of target inhibition and how they contribute to the lethal action of these important drugs, we demonstrate that beta-lactams do more than just inhibit the PBPs as is commonly believed. Rather, they induce a toxic malfunctioning of their target biosynthetic machinery involving a futile cycle of cell wall synthesis and degradation, thereby depleting cellular resources and bolstering their killing activity. Characterization of this mode of action additionally revealed a quality control function for enzymes that cleave bonds in the cell wall matrix. The results thus provide insight into the mechanism of cell wall assembly and suggest how best to interfere with the process for future antibiotic development.
Topics: Amdinocillin; Anti-Bacterial Agents; Cell Wall; Escherichia coli; Glycoside Hydrolases; Penicillin-Binding Proteins; Peptidoglycan; beta-Lactams
PubMed: 25480295
DOI: 10.1016/j.cell.2014.11.017 -
Nature Communications Sep 2018There is urgent need to develop novel treatment strategies to reduce antimicrobial resistance. Collateral sensitivity (CS), where resistance to one antimicrobial...
There is urgent need to develop novel treatment strategies to reduce antimicrobial resistance. Collateral sensitivity (CS), where resistance to one antimicrobial increases susceptibility to other drugs, might enable selection against resistance during treatment. However, the success of this approach would depend on the conservation of CS networks across genetically diverse bacterial strains. Here, we examine CS conservation across diverse Escherichia coli strains isolated from urinary tract infections. We determine collateral susceptibilities of mutants resistant to relevant antimicrobials against 16 antibiotics. Multivariate statistical analyses show that resistance mechanisms, in particular efflux-related mutations, as well as the relative fitness of resistant strains, are principal contributors to collateral responses. Moreover, collateral responses shift the mutant selection window, suggesting that CS-informed therapies may affect evolutionary trajectories of antimicrobial resistance. Our data allow optimism for CS-informed therapy and further suggest that rapid detection of resistance mechanisms is important to accurately predict collateral responses.
Topics: Amdinocillin; Anti-Bacterial Agents; Ciprofloxacin; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Genetic Predisposition to Disease; Genetic Variation; Humans; Microbial Sensitivity Tests; Models, Statistical; Multivariate Analysis; Mutation; Nitrofurantoin; Phylogeny; Trimethoprim; Urinary Tract Infections
PubMed: 30202004
DOI: 10.1038/s41467-018-06143-y -
European Journal of Clinical... Feb 2018Comparative information on diagnosis-related antibiotic prescribing patterns are scarce from primary care within and between countries. To describe and compare... (Observational Study)
Observational Study
Comparative information on diagnosis-related antibiotic prescribing patterns are scarce from primary care within and between countries. To describe and compare antibiotic prescription and routine management of infections in primary care in Latvia (LV), Lithuania (LT) and two study sites in Sweden (SE), a cross-sectional observational study on patients who consulted due to sypmtoms compatible with infection was undetraken. Infection and treatment was detected and recorded by physicians only. Data was collected from altogether 8786 consecutive patients with infections in the three countries. Although the overall proportion of patients receiving an antibiotic prescription was similar in all three countries (LV and LT 42%, SE 38%), there were differences in the rate of prescription between the countries depending on the respective diagnoses. While penicillins dominated among prescriptions (LV 58%, LT 67%, SE 70%), phenoxymethylpenicillin was most commonly prescribed in Sweden (57% of all penicillins), while it was amoxicillin with or without clavulanic acid in Latvia (99%) and Lithuania (85%) respectively. Pivmecillinam and flucloxacillin, which accounted for 29% of penicillins in Sweden, were available neither in Latvia nor in Lithuania. The applied methodology was simple, and provided useful information on differences in treatment of common infections in ambulatory care in the absence of available computerized diagnosis-prescription data. Despite some limitations, the method can be used for assessment of intention to treat and compliance to treatment guidelines and benchmarking locally, nationally, or internationally, just as the point prevalence surveys (PPS) protocols have been used in hospitals all over Europe.
Topics: Adult; Amdinocillin Pivoxil; Amoxicillin; Anti-Bacterial Agents; Bacterial Infections; Clavulanic Acid; Cross-Sectional Studies; Drug Prescriptions; Female; Floxacillin; General Practitioners; Humans; Latvia; Lithuania; Male; Penicillin V; Practice Patterns, Physicians'; Sweden; Young Adult
PubMed: 29218467
DOI: 10.1007/s10096-017-3141-2