Transition coordination compounds with a Schiff base (H2L) derived from the condensation of cephalothin antibiotic with sulfadiazine were synthesized, characterized and screened for antibacterial ...activity. Display omitted
•A new Schiff base using cephalothin antibiotic was prepared.•Cephalothin Schiff base transition metal complexes were prepared.•Magnetic and spectroscopic properties, and antibacterial activity were studied.
Metal(II) coordination compounds of a cephalothin Schiff base (H2L) derived from the condensation of cephalothin antibiotic with sulfadiazine were synthesized. The Schiff base ligand, mononuclear ML(H2O)3 (M(II)=Mn,Co,Ni,Zn) complexes and magnetically diluted dinuclear copper(II) complex CuL(H2O)32 were characterized by several techniques, including elemental and thermal analysis, molar conductance and magnetic susceptibility measurements, electronic, FT-IR, EPR and 1H NMR spectral studies. The cephalothin Schiff base ligand H2L behaves as a dianionic tridentate NOO chelating agent. The biological applications of complexes have been studied on two bacteria strains (Escherichia coli and Staphylococcus aureus) by agar diffusion disc method.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Infections are the second leading cause of global morbidity and mortality, therefore it is highly important to study the antimicrobial agents such as cephalosporins. Cephalothin, an antimicrobial ...agent that belongs to the class of cephalosporins, has bactericidal activity and it is widely used in the Brazilian health system. In literature, some analytical methods are found for the identification and quantification of this drug, which are essential for its quality control, which ensures maintaining the product characteristics, therapeutic efficacy and patient's safety. The aim of this article is to review the available information on analytical methods for cephalothin. Thus, this study presents a literature review on cephalothin and the analytical methods developed for the analysis of this drug in official and scientific papers. It is essential to note that most of the developed methods used toxic and hazardous solvents, which makes necessary industries and researchers choose to develop environmental-friendly techniques, which will contribute to the harmonization of science, human, and environmental health.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An understanding of antibiotic hydrolysis rates is important for predicting their environmental persistence. Hydrolysis rates and Arrhenius constants were determined as a function of pH and ...temperature for three common β-lactam antibiotics, ampicillin, cefalotin, and cefoxitin. Antibiotic hydrolysis rates at pH4–9 at 25°C, 50°C, and 60°C were quantified, and degradation products were identified. The three antibiotics hydrolyzed under ambient conditions (pH7 and 25°C); half-lives ranged from 5.3 to 27d. Base-catalyzed hydrolysis rates were significantly greater than acid-catalyzed and neutral pH hydrolysis rates. Hydrolysis rates increased 2.5- to 3.9-fold for a 10°C increase in temperature. Based on the degradation product masses found, the likely functional groups that underwent hydrolysis were lactam, ester, carbamate, and amide moieties. Many of the proposed products resulting from the hydrolysis of ampicillin, cefalotin, and cefoxitin likely have reduced antimicrobial activity because many products contained a hydrated lactam ring. The results of this research demonstrate that β-lactam antibiotics hydrolyze under ambient pH and temperature conditions. Degradation of β-lactam antibiotics will likely occur over several weeks in most surface waters and over several days in more alkaline systems.
•Three β-lactam antibiotics were studied: ampicillin, cefalotin and cefoxitin.•Antibiotic hydrolysis was investigated under different pH and temperature regimes.•Half-lives were 5.3–27days at pH7 & 25°C; increased 2.5–3.9 fold for each 10°C rise.•Arrehenius coefficients were calculated.•Degradation products showed hydrolysis of lactam, ester, carbamate and amide moieties.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
First generation cephalosporins such cephalothin of cefazolin are indicated for antimicrobial prophylaxis for clean and clean contaminated surgical procedures because its antimicrobial spectrum, ...relative low toxicity and cost. Anesthesia and surgery could alter the pharmacokinetic behavior of different drugs administered perioperative by many mechanisms that affect distribution, metabolism or excretion processes. Intravenous administration of the antimicrobial within 30 and 60 min before incision is recommended in order to reach therapeutic serum and tissue concentrations and redosing is recommended if the duration of the procedure exceeds two half-life of the antimicrobial. To the author's knowledge there are no pharmacokinetic studies of cephalothin in dogs under anesthesia/surgery conditions. The aim of this study was (1) to evaluate the pharmacokinetics of cephalothin in anesthetized dogs undergoing ovariohysterectomy by a nonlinear mixed-effects model and to determine the effect of anesthesia/surgery and other individual covariates on its pharmacokinetic behavior; (2) to determine the MIC and conduct a pharmacodynamic modeling of time kill curves assay of cephalothin against isolates of Staphylococcus spp. isolated from the skin of dogs; (3) to conduct a PK/PD analysis by integration of the obtained nonlinear mixed-effects models in order to evaluate the antimicrobial effect of changing concentrations on simulated bacterial count; and (4) to determine the PK/PD endpoints and PK/PDco values in order to predict the optimal dose regimen of cephalothin for antimicrobial prophylaxis in dogs. Anesthesia/surgery significantly reduced cephalothin clearance by 18.78%. Based on the results of this study, a cephalothin dose regimen of 25 mg/kg q6h by intravenous administration showed to be effective against Staphylococcus spp. isolates with MIC values ≤2 μg/mL and could be recommended for antimicrobial prophylaxis for clean surgery in healthy dogs.
•Anesthesia/surgery reduced cephalothin clearance after IV administration of 25 mg/kg in dogs.•Tentative ECOFFs of Staphylococcus aureus and coagulase negative staphylococci were 2 and 0.5 μg/mL.•A cephalothin IV dose of 25 mg/kg q6h is recommended for antimicrobial prophylaxis against Staphylococcus spp.•PK/PDco of the recommended cephalothin dose regimen was 2 μg/mL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A Swedish patient of Indian origin traveled to New Delhi, India, and acquired a urinary tract infection caused by a carbapenem-resistant Klebsiella pneumoniae strain that typed to the sequence type ...14 complex. The isolate, Klebsiella pneumoniae 05-506, was shown to possess a metallo-beta-lactamase (MBL) but was negative for previously known MBL genes. Gene libraries and amplification of class 1 integrons revealed three resistance-conferring regions; the first contained bla(CMY-4) flanked by ISEcP1 and blc. The second region of 4.8 kb contained a complex class 1 integron with the gene cassettes arr-2, a new erythromycin esterase gene; ereC; aadA1; and cmlA7. An intact ISCR1 element was shown to be downstream from the qac/sul genes. The third region consisted of a new MBL gene, designated bla(NDM-1), flanked on one side by K. pneumoniae DNA and a truncated IS26 element on its other side. The last two regions lie adjacent to one another, and all three regions are found on a 180-kb region that is easily transferable to recipient strains and that confers resistance to all antibiotics except fluoroquinolones and colistin. NDM-1 shares very little identity with other MBLs, with the most similar MBLs being VIM-1/VIM-2, with which it has only 32.4% identity. As well as possessing unique residues near the active site, NDM-1 also has an additional insert between positions 162 and 166 not present in other MBLs. NDM-1 has a molecular mass of 28 kDa, is monomeric, and can hydrolyze all beta-lactams except aztreonam. Compared to VIM-2, NDM-1 displays tighter binding to most cephalosporins, in particular, cefuroxime, cefotaxime, and cephalothin (cefalotin), and also to the penicillins. NDM-1 does not bind to the carbapenems as tightly as IMP-1 or VIM-2 and turns over the carbapenems at a rate similar to that of VIM-2. In addition to K. pneumoniae 05-506, bla(NDM-1) was found on a 140-kb plasmid in an Escherichia coli strain isolated from the patient's feces, inferring the possibility of in vivo conjugation. The broad resistance carried on these plasmids is a further worrying development for India, which already has high levels of antibiotic resistance.
Serine active-site β-lactamases hydrolyze β-lactam antibiotics through the formation of a covalent acyl-enzyme intermediate followed by deacylation via an activated water molecule. Carbapenem ...antibiotics are poorly hydrolyzed by most β-lactamases owing to slow hydrolysis of the acyl-enzyme intermediate. However, the emergence of the KPC-2 carbapenemase has resulted in widespread resistance to these drugs, suggesting it operates more efficiently. Here, we investigated the unusual features of KPC-2 that enable this resistance. We show that KPC-2 has a 20,000-fold increased deacylation rate compared with the common TEM-1 β-lactamase. Furthermore, kinetic analysis of active site alanine mutants indicates that carbapenem hydrolysis is a concerted effort involving multiple residues. Substitution of Asn170 greatly decreases the deacylation rate, but this residue is conserved in both KPC-2 and non-carbapenemase β-lactamases, suggesting it promotes carbapenem hydrolysis only in the context of KPC-2. X-ray structure determination of the N170A enzyme in complex with hydrolyzed imipenem suggests Asn170 may prevent the inactivation of the deacylating water by the 6α-hydroxyethyl substituent of carbapenems. In addition, the Thr235 residue, which interacts with the C3 carboxylate of carbapenems, also contributes strongly to the deacylation reaction. In contrast, mutation of the Arg220 and Thr237 residues decreases the acylation rate and, paradoxically, improves binding affinity for carbapenems. Thus, the role of these residues may be ground state destabilization of the enzyme-substrate complex or, alternatively, to ensure proper alignment of the substrate with key catalytic residues to facilitate acylation. These findings suggest modifications of the carbapenem scaffold to avoid hydrolysis by KPC-2 β-lactamase.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Removing cephalosporin contaminants from aquatic environments is of great concern because of the hazards they pose to the environment and human health. In this study, a Ce-PbO2 anode with a SnO2-Sb ...intermediate layer was fabricated using an electrochemical deposition method and used for the electrocatalytic oxidation of cephalosporin antibiotics. Scanning electron microscopy (SEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) confirmed the successful preparation of the Ce-PbO2 anode and revealed that Ce doping resulted in a highly stable structure and crystallinity of the PbO2 crystals. Moreover, the Ce-PbO2 anode exhibited excellent electrochemical performance with higher oxygen evolution potential (1.56 V), larger electroactive surface area (1.104 C cm−2), smaller corrosion current density (1.796 × 10−4 A cm−2), and higher hydroxyl radical (•OH) yield (8.64 mM min−1 m−2) compared with the intermediate layer and PbO2 anode. The effects of major operating parameters, including current density (20–80 mA cm−2), electrolyte concentration (0.050–0.125 M), initial concentration of target compounds (5–75 mg L−1), and pH (2−10) on the removal efficiencies of cefradine (RAD), and cephalothin (CEP) at the Ce-PbO2 electrode were investigated. The research results illustrated that when electrolysis was carried out for 90 min at the optimal current density of 40 mA cm−2, an initial concentration of 50 mg L−1, and an electrolyte concentration of 0.10 M, the removal efficiency of RAD and CEP were higher than 99%. Additionally, the degradation process followed pseudo-first-order kinetics. The total organic carbon (TOC) removal efficiency of RAD and CEP was 60.6% and 68.2% after 240 min, respectively, under the optimal conditions. The energy consumption for RAD and CEP degradation was 1.74 and 3.04 kWh g−1 TOC, respectively. In addition, the Ce-PbO2 electrode exhibited good stability over nine consecutive cycles. Using UPLC-MS, the intermediate products of RAD and CEP were confirmed, and the degradation intermediates were completely oxidized to CO2, H2O, and inorganic ions (SO42-, NO3-). During electrolysis, the intermediate toxicity was studied using Escherichia coli growth inhibition tests, and the growth inhibition rate was calculated. Considering these results, the Ce-PbO2 anode could be utilized to treat wastewater containing cephalosporin antibiotics with high efficiency.
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•A high-performance Ce-PbO2 electrode was fabricated via electrochemical deposition method.•Ce-PbO2 electrode has high electrocatalytic activity and stability.•Electrochemical degradation of cefradine and cephalothin followed pseudo-first-order kinetics.•The intermediate products and degradation pathways of cefradine and cephalothin were proposed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Boronic acids have proved to be promising selective inhibitors of β-lactamases, acting as transition state analogues. Starting from a previously described nanomolar inhibitor of AmpC β-lactamase, ...three new inhibitors were designed to gain interactions with highly conserved residues, such as Asn343, and to bind more tightly to the enzyme. Among these, one was obtained by stereoselective synthesis and succeeded in placing its anionic group into the carboxylate binding site of the enzyme, as revealed by X-ray crystallography of the complex inhibitor/AmpC. Nevertheless, it failed at improving affinity, when compared to the lead from which it was derived. The origins of this structural and energetic discrepancy are discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
(1) Background: Staphylococcus aureus (S. aureus) is one of the most frequent causes of biofilm-associated infections. With the emergence of antibiotic-resistant, especially methicillin-resistant S. ...aureus (MRSA), there is an urgent need to discover novel inhibitory compounds against this clinically important pathogen. In this study, we evaluated the antimicrobial and anti-biofilm activity of 11 compounds, including phenyl propenes and phenolic aldehydes, eugenol, ferulic acid, sinapic acid, salicylaldehyde, vanillin, cinnamoyl acid, and aldehydes, against drug-resistant S. aureus isolates. (2) Methods: Thirty-two clinical S. aureus isolates were obtained from Alkhidmat Diagnostic Center and Blood Bank, Karachi, Pakistan, and screened for biofilm-forming potential, and susceptibility/resistance against ciprofloxacin, chloramphenicol, ampicillin, amikacin, cephalothin, clindamycin, streptomycin, and gentamicin using the Kirby-Bauer disk diffusion method. Subsequently, 5 representative clinical isolates were selected and used to test the antimicrobial and anti-biofilm potential of 11 compounds using both qualitative and quantitative assays, followed by qPCR analysis to examine the differences in the expression levels of biofilm-forming genes (ica-A, fnb-B, clf-A and cna) in treated (with natural compounds and their derivatives) and untreated isolates. (3) Results: All isolates were found to be multi-drug resistant and dominant biofilm formers. The individual Minimum Inhibitory Concentration (MIC) of natural compounds and their analogues ranged from 0.75−160 mg/mL. Furthermore, the compounds, Salicylaldehyde (SALI), Vanillin (VAN), α-methyl-trans-cinnamaldehyde (A-MT), and trans-4-nitrocinnamic acid (T4N) exhibited significant (15−92%) biofilm inhibition/reduction percentage capacity at the concentration of 1−10 mg/mL. Gene expression analysis showed that salicylaldehyde, α-methyl-trans-cinnamaldehyde, and α-bromo-trans-cinnamaldehyde resulted in a significant (p < 0.05) downregulation of the expression of ica-A, clf-A, and fnb-A genes compared to the untreated resistant isolate. (4) Conclusions: The natural compounds and their analogues used in this study exhibited significant antimicrobial and anti-biofilm activity against S. aureus. Biofilms persist as the main concern in clinical settings. These compounds may serve as potential candidate drug molecules against biofilm forming S. aureus.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Acinetobacter species show high levels of intrinsic resistance to many antibiotics. The major protein species in the outer membrane of Acinetobacter baumannii does not belong to the high-permeability ...trimeric porin family, which includes Escherichia coli OmpF/OmpC, and instead is a close homolog of E. coli OmpA and Pseudomonas aeruginosa OprF. We characterized the pore-forming function of this OmpA homolog, OmpAAb, by a reconstitution assay. OmpAAb produced very low pore-forming activity, about 70-fold lower than that of OmpF and an activity similar to that of E. coli OmpA and P. aeruginosa OprF. The pore size of the OmpAAb channel was similar to that of OprF, i.e., about 2 nm in diameter. The low permeability of OmpAAb is not due to the inactivation of this protein during purification, because the permeability of the whole A. baumannii outer membrane was also very low. Furthermore, the outer membrane permeability to cephalothin and cephaloridine, measured in intact cells, was about 100-fold lower than that of E. coli K-12. The permeability of cephalothin and cephaloridine in A. baumannii was decreased 2- to 3-fold when the ompAAb gene was deleted. These results show that OmpAAb is the major nonspecific channel in A. baumannii. The low permeability of this porin, together with the presence of constitutive β-lactamases and multidrug efflux pumps, such as AdeABC and AdeIJK, appears to be essential for the high levels of intrinsic resistance to a number of antibiotics.
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