Antistaphylococcal Activity Research Articles

Development of Mangifera indica leaf extract incorporated carbopol hydrogel and its antibacterial efficacy against Staphylococcus aureus.

Staphylococcus aureus is a major pathogen causing skin infections and currently treated with topical antibiotic preparations like bacitracin, triple antibiotic ointment (neomycin, polymixin B, and bacitracin), gentamicin or mupirocin. However, their efficacies are restricted when the infections are caused by drug resistant strains. There is an imperative need for new antibacterial compounds for the management of S. aureus topical infections. Maginfera indica (mango) is reported for its antibacterial efficacy in many traditional plant based medicines. In this study we tested the antibacterial efficacy of the methanol extract of mango leaf against SA113 and S. aureus clinical strains. Mango leaf extract (MLE) was found to be an effective anti-staphylococcal agent, non-mutagenic, and contains phytochemicals such as tannins, saponins, flavanoids, phenols, and coumarins. Further, the mango leaf extract (from stock MLE concentration of 130 mg/ml) containing carbopol hydrogel (MLEC) was prepared and characterized further for biocompatibility, rheological and anti-staphylococcal activities. The antibacterial activity of MLEC hydrogel against S. aureus strains was verified using in vitro and ex vivo porcine skin model. Our results demonstrated MLEC hydrogel formulation may act as superior alternative to currently available topical antiseptic/antibiotic formulations for the treatment of drug resistant staphylococcal infections.

Cinnamomum zeylanicum, Dichrostachys glomerata and three other plants had anti-staphylococcal and antibiotic-modifying activity against drug-resistant phenotypes

Cinnamomum zeylanicum, Dichrostachys glomerata and three other plants had anti-staphylococcal and antibiotic-modifying activity against drug-resistant phenotypes

IN VITRO ANTIBACTERIAL ACTIVITY OF MEDICINAL PLANTS IN THE CENTRAL NORTH OF MOROCCO: A POSSIBLE SOURCE OF ALTERNATIVE DRUGS AGAINST METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS

Objective: The present study aims the investigation of the antimicrobial potential of medicinal plants selected in the central north of Morocco against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis strain often involved in dermatitis.
 Methods: Structured interviews were carried out among 91 herbalists and traditional healers through a specific information questionnaire, the in vitro susceptibility of Staphylococcus strains award ethanol extracts was evaluated using the well-diffusion assay, while the agar-microdilution method was used to determinate the minimal inhibitory concentrations (MIC). The total phenolic and flavonoids contents of all tested extracts were also determined.
 Results: Based on the ethnobotanical survey, a total of 55 plant species belonging to 30 families were mentioned. The Lamiaceae family was the most represented (18.80%) followed by the Apiaceae family (10.90%). Leaves (45.00%) were the favored used part. Decoction method (48.53%) was the most frequently used to prepare remedies that are taken externally (75.00%). Nine of the 17 most selected species have shown an effective antistaphylococcal activity; the most active extracts were Punica granatum and Rhamnus alaternus with MIC values ranging between 0.25 mg/ml and 2.00 mg/ml.
 Conclusion: The current data confirm the good antistaphylococcal activity of P. granatum and R. alaternus and suggest that these species could constitute a promoter source for antistaphylococcal drugs with deeply studies.

Efficacy of silver nanoparticles against multidrug resistant clinical Staphylococcus aureus isolates from Nigeria

ABSTRACTMultidrug resistant (MDR) S. aureus infections continue to account for excess mortality in hospital and community settings and constitute a rising global health problem. However, data on the efficacy and mechanism of actions of alternative solutions like silver nanoparticles in developing countries are lacking. This study investigated anti-staphylococcal activity of silver nanoparticles (AgNP) against local strains from Nigeria. A total 119 clinical isolates of S. aureus from five Nigerian laboratories categorized as MRSA (n = 52) and MSSA (n = 67) by PCR were studied. The MIC of AgNP produced by chemical reduction method and characterized by surface plasmon resonance absorbance and size equivalence by scanning electron microscopy was determined by microbroth dilution method. Its effect on protease activity and plasmids were also investigated. Baseline characteristics of the isolates revealed MDR phenotype of the isolates, carriage of diverse plasmids (15–32 kb) among the MDR MSSA, and mean extracellular protease activity of 24.8–55.7 U/mL. The chemically synthesized AgNP had a peak absorbance at 400 nm with a size equivalence of 4.58 nm. The MICs of AgNP against the isolates were 4.7 μg/mL and 4.9 μg/mL, respectively, for MRSA and MSSA (P > 0.05). The bactericidal effect of AgNP at 2.5–5 μg/mL on the MSSA and MRSA isolates was observed at 2.7–5.5 h post exposure in vitro. Further analysis revealed plasmid eviction in the MDR MSSA isolates exposed to 5 μg/mL AgNP and dose-dependent reduction in extracellular protease activity by 84.6–93.1%. Hemolysis of human erythrocytes by AgNP was not observed at the MIC range. Conclusion: This study revealed safety and efficacy of AgNP against clinical MDR S. aureus isolates from Nigeria, using plasmid eviction and protease inhibition as mechanisms of action.

The Ability of Lytic Staphylococcal Podovirus vB_SauP_phiAGO1.3 to Coexist in Equilibrium With Its Host Facilitates the Selection of Host Mutants of Attenuated Virulence but Does Not Preclude the Phage Antistaphylococcal Activity in a Nematode Infection Model.

Phage vB_SauP_phiAGO1.3 (phiAGO1.3) is a polyvalent Staphylococcus lytic podovirus with a 17.6-kb genome (Gozdek et al., 2018). It can infect most of the Staphylococcus aureus human isolates of dominant clonal complexes. We show that a major factor contributing to the wide host range of phiAGO1.3 is a lack or sparcity of target sites for certain restriction-modification systems of types I and II in its genome. Phage phiAGO1.3 requires for adsorption β-O-GlcNAcylated cell wall teichoic acid, which is also essential for the expression of methicillin resistance. Under certain conditions an exposure of S. aureus to phiAGO1.3 can lead to the establishment of a mixed population in which the bacteria and phages remain in equilibrium over multiple generations. This is reminiscent of the so called phage carrier state enabling the co-existence of phage-resistant and phage-sensitive cells supporting a continuous growth of the bacterial and phage populations. The stable co-existence of bacteria and phage favors the emergence of phage-resistant variants of the bacterium. All phiAGO1.3-resistant cells isolated from the phage-carrier-state cultures contained a mutation inactivating the two-component regulatory system ArlRS, essential for efficient expression of numerous S. aureus virulence-associated traits. Moreover, the mutants were unaffected in their susceptibility to infection with an unrelated, polyvalent S. aureus phage of the genus Kayvirus. The ability of phiAGO1.3 to establish phage-carrier-state cultures did not preclude its antistaphylococcal activity in vivo in an S. aureus nematode infection model. Taken together our results suggest that phiAGO1.3 could be suitable for the therapeutic application in humans and animals, alone or in cocktails with Kayvirus phages. It might be especially useful in the treatment of infections with the majority of methicillin-resistant S. aureus strains.

Phytochemical analysis of Brasolia, Elleanthus, and Sobralia. Three genera of orchids with antibacterial potential against Staphylococcus aureus

The purpose of the study was to determine the chemical composition of extracts from three species of orchids: Brasolia cattleya, Elleanthus oliganthus and Sobralia powellii, all belonging to the Sobralieae tribe, evaluate their antistaphylococcal activity and assess possible toxicity towards eukaryotic cells on the model organism Caenorhabditis elegans. The chemical composition of the methanolic extracts from those plants was tested with the use of UHPLC-ESI-MS/MS method. The phytochemical analyses of the extracts revealed presence of three main groups of secondary metabolites: phenolic derivatives, flavonoid glycosides and triterpenoid saponins. In our studies, the presence of C-O-glycosides of methoxylated flavones and ester derivatives of arbutin were found for the first time in the Orchidaceae family. The extracts were investigated for antimicrobial activity against five Staphylococcus aureus strains, including four strains isolated from hospital patients. The antimicrobial activity of the orchid extracts was estimated by the Minimum Inhibitory Concentration (MIC) and the Minimal Bactericidal Concentration (MBC) determined by Broth Microdilutions method. All of the examined extracts showed strong antimicrobial activity against the S. aureus strains. The MBC values ranged from 0.25 to 0.75 mg of fresh weight (fw)/mL. To assess the toxicity of the extracts we used cultures of C. elegans, wild-type N2 Bristol strain. The extracts occurred to be nontoxic towards C. elegans in a broad range of concentration (from 0.75 mg to 50 mg fw/mL) after 24-hour incubation. The maximum extract dose tested on C. elegans was 10 times higher than the effective bactericidal concentration for S. aureus. The obtained results allow us to conclude that the methanolic extracts from B. cattleya, E. oliganthus and S. powellii are of a potential use for treatment of bacterial infections caused by the antibiotic-resistant strains of S. aureus.

In vivo anti-staphylococcal activity of roselle (Hibiscus sabdariffa L.) calyx extract in Drosophila model of infection

Introduction: The emergence of antibiotic-resistant Staphylococcus aureus is a major threat for worldwide communities. To overcome such serious problem, the discovery of novel antibacterial agents through exploration of diverse potential sources is essential. The aim of this research was to investigate the in vivo anti-staphylococcal activity of roselle (Hibiscus sabdariffa L.) calyx extract against S. aureus in fruit flies (Drosophila melanogaster) model of infection. Methods: Roselle calyces were dried and extracted with ethanol using maceration method. Wildtype fruit flies were infected with S. aureus and subjected to survival assay, bacterial load examination, and gene expression analysis, in the presence or absence of roselle calyx extract. Survival and bacterial load analysis were subsequently performed on immunodeficient fruit flies using similar protocols. Results: Reduction of host survivorship accompanied by increasing level of bacterial proliferation was observed in group of wildtype fruit flies infected with S. aureus. These phenotypic events were further augmented in mutant flies devoid of component for antibacterial immune responses. Nevertheless, reduction of bacterial load and improvement of host survival were demonstrated in either wildtype or immunodeficient fruit flies upon treatment with roselle calyx extract after bacterial challenge, irrespective of immune status. Conclusion: Collectively, our results demonstrated the in vivo antibacterial activity of roselle calyx extract against S. aureus in Drosophila model of infection and this was not due to induction of immune response in the host.

Anti-staphylococcal activity of bacteriocins of food isolates Enterococcus hirae LD3 and Lactobacillus plantarum LD4 in pasteurized milk.

Bacteriocins of Enterococcus hirae LD3 and Lactobacillus plantarum LD4 have been applied in milk for growth inhibition of Staphylococcus aureus. The enumeration of S. aureus cells in nutrient broth and milk was found log10 9.7 and 10.2CFU/mL, respectively, whereas it was reduced with increasing concentration of bacteriocins suggesting loss of cell viability. The lethal concentration (LC50) of enterocin LD3 and plantaricin LD4 against S. aureus was 160 and 220µg/mL, respectively. Bacteriocin-treated cells were stained red with propidium iodide (PI) indicating dead cells further confirms bactericidal nature. The enterocin LD3-treated cells showed higher infrared absorbance at 1451.82cm- 1 corresponding to phospholipids suggesting membrane-acting nature of the bacteriocin. However, plantaricin LD4-treated cells did not show such alterations suggesting different mode of action. Both bacteriocins caused disruption and shrinkage of target cells, and leakage of intracellular contents as observed in transmission electron microscope (TEM). The present study suggests killing of S. aureus in milk, therefore, enterocin LD3 and plantaricin LD4 may be applied in biopreservation of milk and related food products.

ПОРІВНЯЛЬНИЙ АНАЛІЗ ЦИТОСТАТИЧНОЇ ТА АНТИБАКТЕРІАЛЬНОЇ АКТИВНОСТІ ЕКСТРАКТІВ АМБРОЗІЇ ПОЛИНОЛИСТНОЇ Й ІНШИХ ЛІКАРСЬКИХ РОСЛИН ТА ВИЗНАЧЕННЯ ЛІТИЧНОЇ АКТИВНОСТІ ЕКСТРАКТІВ АМБРОЗІЇ ПОЛИНОЛИСТНОЇ

The article is devoted to the important problem of the search of herbal preparations with high antibacterial, cytostatic and lithic activity. The plants such as Ambrosia artemisiifolia, which belongs to the family of Aystrou, are promising in this direction. The aim of the presented work is to study the antibacterial, cytostatic and lithic activity of water extracts of Ambrosia polynolithic and conduct a comparative analysis of these properties with other medicinal plants. Determining that the lectin extract from the green shoots (until flowering) of Ambrosia artemisiifolia does not agglutinate red blood cells, makes it possible to consider this raw material as a potential drug in pharmacology. Investigation of cytostatic activity by the method of Ivanov and Bystrova enabled to establish a place of ambrosia among already well-known medicinal plants. The cytostatic activity of the investigated plants can be represented by the following series in the order of reduction: Chelidónium május, Ambrosia artemisiifolia, Vinca minor, Viscum album. The establishment of antibacterial activity allowed to confirm the presence of anti-staphylococcal activity of the water extract of ambrosia and its significant effect on the colon. Anti-staphylococcus activity of the water extract of Ambrosia artemisiifolia is close to Viscum album and Chelidónium május. The antibacterial effect against Proteus vulgaris was the highest in the extract of аmbrosiа shoots, compared with other medicinal plants studied. Taking into account the phylogenetic method, it could be expected that the plants of the Aystroe family may have a lithic activity with respect to the concrements that are formed in the kidneys of man. So, a study was conducted on the lithic activity of polystyrene embryos and it was found that Ambrosia artemisiifolia has a high lithic activity in relation to urate and oxalate concretions.

Research to antimicrobial action characteristics of antiseptics under protein loading to microorganisms

Setting of rational antibacterial therapy for treatment of the used for setting fire diseases of oral cavity and throat is the issue enough of the day, the decision of that depends on the row of factors that cause implicit interest of practical medicine. Infectious diseases and purulent-inflammatory processes of microbial origin play an important role in shaping the main indicators of health in Ukraine. Unfortunately, the use of systemic antimicrobial drugs by doctors, in most cases, is empirical, without taking into account regional tendencies of resistance. It can promote the spread of strains of microorganisms with multiple resistance to them, the emergence of outbreaks of hospital infections and increase the risk of severe complications. The aim of this work is to investigate the antimicrobial activity of antiseptic drugs such as septefril, sebidin, agisept on clinical strains of S.aureus. The experiment made in presence of the unfavorable factors (5% and 10 % protein solution). Domestic antiseptic drug septefril in its composition antiseptic decamethoxin®. The basis of the drug itself is chlorhexidine. The basis of the drug agisept is amylmetacresol. The antimicrobial activity of the agisept at 5% protein loading practically did not change. Reduction of anti-staphylococcal activity by 2.3 times observed in the preparation of septefril. The highest decrease in activity observed 6 times in the drug itself. At 10% protein load, the antistaphylococcal activity decreased by seventh-one times in septefril, 1.3 times in agisept. The greatest decrease in activity, in 10.7 times, was at the same time. Thus, we have established a reduction in the antimicrobial activity of antiseptic drugs in the presence of serum protein, but the level of action remained quite high with respect to clinical strains of microorganisms.

Antistaphylococcal activity of carbonic acid extract of hops

The fight against staphylococcal infection, increasing the effectiveness of methods of prevention and treatment of diseases of staphylococcal etiology is of interest to scientists and practitioners, both in Ukraine and around the world. The urgency of this problem is growing rapidly, as there is a tendency to increase the resistance of not only staphylococci, but also other gram-positive bacteria. The spread of methicillin-resistant staphylococci restricts the choice of antibiotics for the treatment of diseases of staphylococcal etiology. Staphylococcus aureus is the most common and dangerous type, which is one of the main factors of purulent-inflammatory lesions of the skin and mucous membranes. As a result of mutations, pathogenic staphylococci acquired resistance to antibacterial drugs. The main disadvantage of modern antibiotics is their non-selectivity. As a result of mutations, pathogenic staphylococci acquired resistance to antibacterial drugs. The main disadvantage of modern antibiotics is their non-selectivity. One of the unique and promising medicinal plants, which contains a rich complex of biologically active substances (BAS), is common hops (Humulus lupulus L.). The complex of BAS (flavonoids, hormones, vitamins, bitter, phenolic compounds, essential oils) causes anti-inflammatory, bactericidal, hyposensitizing and analgesic action of hops. The purpose of this work is to determine the antistaphylococcal activity of the carbon dioxide extract of hops and to justify the development on its basis of new antimicrobial agents for the prevention and treatment of infectious and purulent-inflammatory diseases. The following methods were used: microbiological (method of diffusion into agar (well method)) and mathematical and statistical. The high antimicrobial activity of the carbon dioxide extract of hops has been established for museum test strains of the genus Staphylococcus. The results of the studies testify to the prospects of further study of the bactericidal properties of the extract of hops carbon dioxide with the aim of creating effective antimicrobial agents on its basis for the prevention and treatment of infectious and purulent-inflammatory diseases of staphylococcal etiology.

Anti-staphylococcal activity and antibiotic-modulating effect of Olax subscorpioidea, Piper guineense, Scorodophloeus zenkeri, Fagara leprieurii, and Monodora myristica against resistant phenotypes

Anti-staphylococcal activity and antibiotic-modulating effect of Olax subscorpioidea, Piper guineense, Scorodophloeus zenkeri, Fagara leprieurii, and Monodora myristica against resistant phenotypes

Isolation of a Lactococcus lactis Strain Producing Anti-staphylococcal Bacteriocin.

Bacteriocin is ribosomally synthesized by bacteria and inhibits closely related species. In this study we aimed at isolating lactic acid bacteria producing bacteriocin presenting anti-staphylococcal activity. A Lactococcus lactis strain was isolated from kimchi for the purpose and identified by 16S rRNA gene sequencing. As preliminary tests, optimal culture conditions, stabilities against heat, solvents, and enzymes treatments, and type of action (bacteriostatic or bactericidal) of the bacteriocin were investigated. The optimal culture conditions for production of the bacteriocin were MRS broth medium and 25℃ and 30℃ culture temperatures. The bacteriocin was acidic and the activity was abolished by a protease treatment. Its stability was maintained at 100℃ for 15 min and under treatments of various organic solvents such as methanol, ethanol, acetone, acetonitrile, and chloroform. Finally, the bacteriocin showed bactericidal action against Staphylococcus aureus where 200 AU/mL of the bacteriocin decreased the viable cell count (CFU/mL) of S. aureus by 2.5 log scale, compared with a control (no bacteriocin added) after 4-h incubation.

Antilisterial and antistaphylococcal activity of a Lactococcus lactis strain isolated from Brazilian fresh Minas cheese

Abstract Lactococcus lactis QMF 11, isolated from Brazilian fresh cheese, produces bacteriocin like inhibitory substances (bac+). To evaluate L. lactis QMF11 possible application on biopreservation systems of dairy food, co‐inoculation studies were performed in pasteurized milk (8 °C, 10 days) targeting the inhibition of Listeria monocytogenes ATCC 7644 or Staphylococcus aureus ATCC 25923. Lactobacillus sakei ATCC 15521 was used as a negative control for bacteriocin production (bac−). L. monocytogenes and S. aureus reached 8 log CFU ml−1 and 5.4 log CFU ml−1 in monoculture, respectively, compared to <2.3 log CFU ml−1 and 4.7 log CFU ml−1 in co‐culture with L. lactis QMF 11. Instead, in the presence of the bac−, L. monocytogenes population reached 7.3 log CFU ml−1 and S. aureus populations 5.5 log CFU ml−1. These results indicate that L. lactis QMF11 may have potential for be use as biopreservative culture in dairy products, mainly because of its antilisterial activity.Practical applicationsThere is a renewed interest in the use protective bacterial cultures or their metabolites to guarantee the microbiological safety and to extend the shelf life of dairy products, in a process called biopreservation. The research in this area has been leveraged by consumers demand for naturally preserved foods. Dairy products are natural niches for Lactococcus lactis strains, and these bacteria have been associated with food production and preservation since ancient times. As a dominant species in dairy ecosystems, L. lactis strains are very interesting because they are not likely to require regulatory approval for practical application as bioprotective cultures.

The antimetabolite 3-bromopyruvate selectively inhibits Staphylococcus aureus

Increased antibacterial resistance jeopardizes current therapeutic strategies to control infections, soliciting the development of novel antibacterial drugs with new mechanisms of action. This study reports the discovery of potent and selective antistaphylococcal activity of 3-bromopyruvate (3BP), an antimetabolite in preclinical development as an anticancer drug. 3BP showed bactericidal activity against Staphylococcus aureus, with active concentrations comparable with those reported to be effective against cancer cells. In contrast, no relevant activity was observed against other ESKAPE bacteria (Enterococcus faecium, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.). The antistaphylococcal activity of 3BP was confirmed using a panel of human and veterinary strains, including multi-drug-resistant isolates. 3BP showed highest antibacterial activity under conditions that increase its stability (acidic pH) or promote S. aureus fermentative metabolism (anaerobiosis), although 3BP was also able to kill metabolically inactive cells. 3BP showed synergism with gentamicin, and also disrupted preformed S. aureus biofilms at concentrations only slightly higher than those inhibiting planktonic cells. This study unravels novel antibacterial and antibiofilm activities for the anticancer drug 3BP, paving the way for further preclinical studies.

A novel bi-functional chalcone inhibits multi-drug resistant Staphylococcus aureus and potentiates the activity of fluoroquinolones

Staphylococcus aureus is the leading cause of bacteraemia and the dwindling supply of effective antibacterials has exacerbated the problem of managing infections caused by this bacterium. Isoliquiritigenin (ISL) is a plant flavonoid that displays therapeutic potential against S. aureus. The present study identified a novel mannich base derivatives of ISL, IMRG4, active against Vancomycin intermediate S. aureus (VISA). IMRG4 damages the bacterial membranes causing membrane depolarization and permeabilization, as determined by loss of salt tolerance, flow cytometric analysis, propidium idodie and fluorescent microscopy. It reduces the intracellular invasion of HEK-293 cells by S. aureus and decreases the staphylococcal load in different organs of infected mice models. In addition to anti-staphylococcal activity, IMRG4 inhibits the multidrug efflux pump, NorA, which was determined by molecular docking and EtBr efflux assays. In combination, IMRG4 significantly reduces the MIC of norfloxacin for clinical strains of S. aureus including VISA. Development of resistance against IMRG4 alone and in combination with norfloxacin was low and IMRG4 prolongs the post-antibiotic effect of norfloxacin. These virtues combined with the low toxicity of IMRG4, assessed by MTT assay and haemolysis, makes it an ideal candidate to enter drug development pipeline against S. aureus.

Disubstituted 4-Chloro-3-nitrophenylthiourea Derivatives: Antimicrobial and Cytotoxic Studies

4-Chloro-3-nitrophenylthioureas 1–30 were synthesized and tested for their antimicrobial and cytotoxic activities. Compounds exhibited high to moderate antistaphylococcal activity against both standard and clinical strains (MIC values 2–64 μg/mL). Among them derivatives with electron-donating alkyl substituents at the phenyl ring were the most promising. Moreover, compounds 1–6 and 8–19 were cytotoxic against MT-4 cells and various other cell lines derived from human hematological tumors (CC50 ≤ 10 μM). The influence of derivatives 11, 13 and 25 on viability, mortality and the growth rate of immortalized human keratinocytes (HaCaT) was observed.

Efficacy of chimeric ectolysin P128 in drug-resistant Staphylococcus aureus bacteraemia in mice.

P128 is a recombinant chimeric ectolysin with potent antistaphylococcal activity. P128 was evaluated as monotherapy and in combination with two standard-of-care (SoC) antibiotics, vancomycin and daptomycin, in mouse models of Staphylococcus aureus bacteraemia. Healthy BALB/c mice were challenged (intraperitoneally) with 109 cfu of MRSA strain COL or USA300 and treated with a single dose of P128 (0.2-10 mg/kg). Drug synergy was tested using a single dose of P128 (0.2 or 2.5 mg/kg) along with sub-therapeutic dose levels of vancomycin (27.5 or 55 mg/kg) or daptomycin (12.5 mg/kg). Bacterial load was checked in peritoneal fluid and in blood, at different time intervals. Synergy against drug-resistant strains was tested using the P128/vancomycin combination against vancomycin-resistant S. aureus (VRSA). In MRSA bacteraemia, P128, vancomycin and daptomycin monotherapy resulted in 31%, 46% and 46% survival, respectively. The P128/vancomycin and P128/daptomycin combinations afforded increased survival of 85% and 88%, respectively. P128 showed a rapid bactericidal effect with a reduction of cfu in both the peritoneal fluid and the blood within 1 h. In VRSA bacteraemia, a mouse-equivalent therapeutic dose of vancomycin (110 mg/kg) failed to rescue animals. P128 (1-20 mg/kg) as monotherapy resulted in dose-dependent efficacy. Survival (37%) with 2.5 mg/kg P128 increased to 63% with the P128/vancomycin combination. P128 exerted a rapid bactericidal effect in vivo and rescued animals from fatal invasive MRSA and VRSA infections. P128/SoC antibiotic combinations exerted a synergistic effect. P128 restored the susceptibility of VRSA to vancomycin. P128 is a novel, potent therapeutic agent for antibiotic-resistant, systemic S. aureus infections.

Relationship of antimicrobial activity and chemical structure of the arylaliphatic aminoalcohol derivatives

Arylaliphatic aminoalcohols appeared to be the new promising class of compounds for the development of antibacterial and antifungal agents. The aim of the presented study was to analyze the «chemical structure-antimicrobial activity» relationship for further activity-directed synthesis of compounds of this class.
 The antimicrobial activity of the compounds was investigated by serial broth dilution method. Primary analysis of the effect of substituents’ structure on the ability of the derivatives to inhibit the growth of test-microorganisms was carried out by empirical method. Molecular structural characteristics of arylaliphatic aminoalcohols (surface area, volume, partition coefficient logP and dipole moment) were calculated by means of «Hyperchem 8.0.8» software. Relationship between the antimicrobial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and molecular characteristics was investigated by correlation analysis using the Spearman test. Statistical processing was performed by «StatSoft Statistica 6.0», the data obtained were evaluated using Chaddock scale.
 The data obtained suggest, that the presence of both antibacterial and antifungal activity in arylaliphatic aminoalcohols depends on the amino group structure and composition of aryl(alkyl)oxy-radical (4-(1,1,3,3-tetramethylbutyl)phenyl, 1-adamantyl, 4-(1-adamantyl)phenyl, 4-phenyl-phenyl or 2,4-ditretbutyl phenyl). The correlation analysis revealed an inverse relationship between the antimicrobial action and surface area, volume, and lipophilicity of compounds. The tightest correlation was found between these parameters and antistaphylococcal activity. Our results indicate the promises of the synthesis, directed to the reducing of the molecule size and lipophilicity of tetramethylbutylphenyl aminoalcohols, for further development of broad-spectrum antimicrobial agents.

Novel Iron-Chelator DIBI Inhibits Staphylococcus aureus Growth, Suppresses Experimental MRSA Infection in Mice and Enhances the Activities of Diverse Antibiotics in vitro.

DIBI, a purpose-designed hydroxypyridinone-containing iron-chelating antimicrobial polymer was studied for its anti-staphylococcal activities in vitro in comparison to deferiprone, the chemically related, small molecule hydroxypyridinone chelator. The sensitivities of 18 clinical isolates of Staphylococcus aureus from human, canine and bovine infections were determined. DIBI was strongly inhibitory to all isolates, displaying approximately 100-fold more inhibitory activity than deferiprone when compared on their molar iron-binding capacities. Sensitivity to DIBI was similar for both antibiotic-resistant and -sensitive isolates, including hospital- and community-acquired (United States 300) MRSA. DIBI inhibition was primarily bacteriostatic in nature at low concentration and was reversible by addition of Fe. DIBI also exhibited in vivo anti-infective activity in two distinct MRSA ATCC43300 infection and colonization models in mice. In a superficial skin wound infection model, topical application of DIBI provided a dose-dependent suppression of infection along with reduced wound inflammation. Intranasal DIBI reduced staphylococcal burden by >2 log in a MRSA nares carriage model. DIBI was also examined for its influence on antibiotic activities with a reference isolate ATCC6538, typically utilized to assess new antimicrobials. Sub-bacteriostatic concentrations of DIBI resulted in Fe-restricted growth and this physiological condition displayed increased sensitivity to GEN, CIP, and VAN. DIBI did not impair antibiotic activity but rather it enhanced overall killing. Importantly, recovery growth of survivors that typically followed an initial sub-MIC antibiotic killing phase was substantially suppressed by DIBI for each of the antibiotics examined. DIBI has promise for restricting staphylococcal infection on its own, regardless of the isolate’s animal source or antibiotic resistance profile. DIBI also has potential for use in combination with various classes of currently available antibiotics to improve their responses.