In vitro antimicrobial activity of a novel compound, Mul-1867, against clinically important bacteria (original) (raw)
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Annals of Clinical Microbiology and Antimicrobials, 2016
Background: There is an urgent need for new antimicrobial compounds to treat various lung infections caused by multidrug-resistant Pseudomonas aeruginosa (MDR-PA). Methods: We studied the potency of Mul-1867 against MDR-PA isolates from patients with cystic fibrosis, chronic obstructive pulmonary disease, and ventilator-associated pneumonia. The minimal inhibitory concentrations (MICs) and minimum biofilm eliminating concentrations (MBECs), defined as the concentrations of drug that kill 50 % (MBEC 50), 90 % (MBEC 90), and 100 % (MBEC 100) of the bacteria in preformed biofilms, were determined by using the broth macrodilution method. Results: Mul-1867 exhibited significant activity against MDR-PA and susceptible control strains, with MICs ranging from 1.0 to 8.0 µg/mL. Mul-1867 also possesses anti-biofilm activity against mucoid and non-mucoid 24-hold MDR-PA biofilms. The MBEC 50 value was equal to onefold the MIC. The MBEC 90 value ranged from two to fourfold the MIC. Moreover, Mul-1867 completely eradicated mature biofilms at the concentrations tested, with MBEC 100 values ranging between 16-and 32-fold the MIC. Mul-1867 was non-toxic to Madin-Darby canine kidney (MDCK) cells at concentrations up to 256 µg/mL. Conclusion: Overall, these data indicate that Mul-1867 is a promising locally acting antimicrobial for the treatment and prevention of P. aeruginosa infections.
In vitro antimicrobial activity of a new antibiotic, MDL 62,879 (GE2270 A)
Antimicrobial Agents and Chemotherapy, 1993
MDL 62,879 (GE2270 A) is a new peptide antibiotic that inhibits protein synthesis through an interaction with elongation factor Tu. MDL 62,879 was very active against gram-positive clinical isolates, particulariy staphylococci and enterococci, for which MICs for 90% of isolates were <0.13 pg/ml. It was equally active against isolates resistant to ji-lactams, erythromycin, gentamicin, and glycopeptides. It also had activity against Mycobacterium tuberculosis. MDL 62,879 had moderate bactericidal activity against staphylococci.
Annals of Clinical Microbiology and Antimicrobials
2007
Background: MUC7 12-mer (RKSYKCLHKRCR), a cationic antimicrobial peptide derived from the human low-molecular-weight salivary mucin MUC7, possesses potent antimicrobial activity in vitro. In order to evaluate the potential therapeutic application of the MUC7 12-mer, we examined the effects of mono-and divalent cations, EDTA, pH, and temperature on its antimicrobial activity. Methods: Minimal Inhibitory Concentrations (MICs) were determined using a liquid growth inhibition assay in 96-well microtiter plates. MUC7 12-mer was added at concentrations of 1.56-50 M. MICs were determined at three endpoints: MIC-0, MIC-1, and MIC-2 (the lowest drug concentration showing 10%, 25% and 50% of growth, respectively). To examine the effect of salts or EDTA, a checkerboard microdilution technique was used. Fractional inhibitory concentration index (FICi) was calculated on the basis of MIC-0. The viability of microbial cells treated with MUC7 12-mer in the presence of sodium or potassium was also determined by killing assay or flow cytometry. Results: The MICs of MUC7 12-mer against organisms tested ranged from 6.25-50 M. For C. albicans, antagonism (FICi 4.5) was observed for the combination of MUC7 12-mer and calcium; however, there was synergism (FICi 0.22) between MUC7 12-mer and EDTA, and the synergism was retained in the presence of calcium at its physiological concentration (1-2 mM). No antagonism but additivity or indifference (FICi 0.55-2.5) was observed for the combination of MUC7 12-mer and each K + , Na + , Mg 2+ , or Zn 2+. MUC7 12-mer peptide (at 25 M) also exerted killing activity in the presence of NaCl, (up to 25 mM for C. albicans and up to 150 mM for E. coli, a physiological concentration of sodium in the oral cavity and serum, respectively) and retained candidacidal activity in the presence of KCl (up to 40 mM). The peptide exhibited higher inhibitory activity against C. albicans at pH 7, 8, and 9 than at pH 5 and 6, and temperature up to 60°C did not affect the activity. Conclusion: MUC7 12-mer peptide is effective anticandidal agent at physiological concentrations of variety of ions in the oral cavity. These results suggest that, especially in combination with EDTA, it could potentially be applied as an alternative therapeutic agent for the treatment of human oral candidiasis.
The need of controlling infectious microbes has increased in the past years due to the increased resistance of the microorganisms towards the antimicrobial agents as a result of the changes in their cellular membrane proteins, ionic channels, and cell surface receptors. Scientists are working their best to offer such an agent that could prove practical to harmful microbes that pose threats to the lives of people. This review focuses on the information about the modes of actions of some antimicrobial agents that are recently discovered, approved or used by scientific laboratories and pharmaceutical companies to make the future studies somewhat easier for the young scientists to make their way through their research works leading to newer drug discoveries with new and improved mechanisms against microbial integrity. Many new drugs have recently been reported to have performed their best against multi-drug resistant Staphylococcus aureus and Pseudomonas, apart from bacterial control several new antifungal and antiviral agents have also been reported that are known to have performed best at clinical levels.
Clinical Microbiology and Infection, 2010
Use of antiseptics and disinfectants is essential in infection control practices in hospital and other healthcare settings. In this study, the in vitro activity of a new promising compound, para-guanidinoethylcalix[4]arene (Cx1), has been evaluated in comparison with hexamidine (HX) and chlorhexidine (CHX), two older cationic antiseptics. The MICs for 69 clinical isolates comprising methicillin-resistant Staphylococcus aureus, methicillin-sensitive S. aureus, coagulase-negative staphylococci (CoNS) (with or without mecA), vancomycin-resistant enterococci, Enterobacteriaceae producing various b-lactamases and non-fermenting bacilli (Pseudomonas aeruginosa, Acinetobacter baumanii, Stenotrophomonas maltophilia) were determined. Cx1 showed similar activity against S. aureus, CoNS and Enterococcus spp., irrespective of the presence of mecA or van genes, or associated resistance genes, with very good activity against CoNS (MIC <1 mg/L).
Antimicrobial activity of MDL 63,246, a new semisynthetic glycopeptide antibiotic
Antimicrobial agents …, 1995
MDL 63,246 is a semisynthetic derivative of the naturally occurring glycopeptide antibiotic MDL 62,476 (A40926). It was more active in vitro against Staphylococcus aureus and coagulase-negative staphylococci than MDL 62,476, teicoplanin, and vancomycin and was more active than mideplanin (MDL 62,873) against some isolates. MDL 63,246 had excellent activity against streptococci and teicoplanin-susceptible enterococci, and it also had in vitro activity against some VanA enterococcal isolates. It was more active than teicoplanin and vancomycin against acute staphylococcal, streptococcal, and enterococcal septicemia in immunocompetent and neutropenic mice. It was highly efficacious in reducing the bacterial load in the hearts of rats in staphylococcal endocarditis experiments and the bacterial load of Staphylococcus epidermidis in a thigh infection model in neutropenic mice. The excellent in vivo activity of MDL 63,246 appears to correlate both with its in vitro antibacterial activity and with its long half-life in rodents.
Scientific reports, 2016
A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60-80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations report...
Directions in the development of modern and promising antimicrobial agents
Biologija
The use of antibiotics is becoming increasingly limited. This is mainly due to the development of resistance to pathogenic bacteria, and, over time, more and more bacteria will become resistant to antimicrobials. This problem inevitably leads to the conclusion that studies into alternative methods of combating pathogens, which are necessary to develop sufficiently reliable and effective therapies for bacterial infections, are indispensable. This review highlights some recent developments in conventional antibiotic and non-antibiotic treatment strategies. It has been shown that traditional antibacterial targets include derivatives of known antibiotic classes, new chemical classes with new targets, as well as unknown or undefined agents with unclear targets. Promising strategies for combating microbial pathogens have been identified, including new targets, namely, toxin secretion systems, biofilm formation, and adhesion mechanisms that affect quorum sensing of microbial populations. I...
Pharmacology of Novel Heteroaromatic Polycycle Antibacterials
Antimicrobial Agents and Chemotherapy, 2003
Heteroaromatic polycycle (HARP) compounds are a novel class of small (M w , 600 to 650) DNA-binding antibacterials. HARP compounds exhibit a novel mechanism of action by preferentially binding to AT-rich sites commonly found in bacterial promoters and replication origins. Noncovalent binding in the minor groove of DNA results in inhibition of DNA replication and DNA-dependent RNA transcription and subsequent bacterial growth. HARP compounds have previously been shown to have potent in vitro activities against a broad spectrum of gram-positive organisms. The present report describes the extensive profiling of the in vitro and in vivo pharmacology of HARP antibacterials. The efficacies of representative compounds (GSQ-2287, GSQ-10547, and GSQ-11203), which exhibited good MIC activity, were tested in murine lethal peritonitis and neutropenic thigh infection models following intravenous (i.v.) administration. All compounds were efficacious in vivo, with potencies generally correlating with MICs. GSQ-10547 was the most potent compound in vitro and in vivo, with a 50% effective dose in the murine lethal peritonitis model of 7 mg/kg of body weight against methicillin-sensitive Staphylococcus aureus (MSSA) and 13 mg/kg against methicillin-resistant S. aureus (MRSA). In the neutropenic mouse thigh infection model, GSQ-11203 reduced the bacterial load (MRSA and MSSA) 2 log units following administration of a 25-mg/kg i.v. dose. In a murine lung infection model, treatment with GSQ-10547 at a dose of 50 mg/kg resulted in 100% survival. In addition to determination of efficacy in animals, the pharmacokinetic and tissue disposition profiles in animals following administration of an i.v. dose were determined. The compounds were advanced into broad safety screening studies, including screening for safety pharmacology, genotoxicity, and rodent toxicity. The results support further development of this novel class of antibiotics. on December 19, 2015 by guest http://aac.asm.org/ Downloaded from FIG. 4. Dose-response curve for GSQ-10547 for determination of its efficacy against MRSA sepsis. The results reflect survival at day 5 after an intraperitoneal injection of a lethal inoculum of MRSA and administration of the test compound at 1 h postinfection. Percent survival data (from 19 individual studies) were fit to a sigmoid maximum effectiveness model by using the WinNonlin (version 4.0) program. The ED 50 (12 mg/kg) and gamma (shape parameter) were determined along with the coefficient of variance (11%).