Structure-activity relationship in the oxazolidinone-quinolone hybrid series: influence of the central spacer on the antibacterial activity and the mode of action

Oxazolidinone-quinolone hybrids, which combine the pharmacophores of a quinolone and an oxazolidinone, were synthesised and shown to be active against a variety of susceptible and resistant Gram-positive and Gram-negative bacteria. The nature of the spacer greatly influences the antibacterial activity by directing the mode of action, that is quinolone- and/or oxazolidinone-like activity. The best compounds in this series have a balanced dual mode of action and overcome all types of resistance, including resistance to quinolones and linezolid, in clinically relevant Gram-positive pathogens.     

Design,synthesis and biological evaluation of spiropyrimidinetriones oxazolidinone derivatives as antibacterial agents

Gram-positive bacteria are among the most common human pathogens associated with clinical infections which range from mild skin infections to sepsis. Resistance towards existing class of drugs by Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE) is a growing concern. There is an urgent need to discover new antibiotics which are active against resistant strains of Gram positive bacteria. We report herein a novel class of spiropyrimidinetrione oxazolidinone derivatives as novel antibacterial agents. Key step towards the synthesis of title compounds involved the use of tert-amino reaction with [1,5]-hydride shift leading to the new CC bond formation. Compound 30n has demonstrated potent antibacterial activity against a panel of Gram-positive microbial strains including MRSA, MRSE, and LNZ and vancomycin resistant strains of E. faecalis. Further, molecular docking studies suggest that 30n has binding mode similar to that of LNZ in 50S RNA ribosome.     

Recent advances in the preclinical evaluation of the topical antibacterial agent REP8839

REP8839 is a synthetic fluorovinylthiophene-containing diaryldiamine that inhibits bacterial methionyl tRNA synthetase (MetRS) and is a new chemical entity that represents a novel pharmacological class. The compound has potent in vitro antibacterial activity against many clinically important Gram-positive bacteria including the major skin pathogens Staphylococcus aureus and Streptococcus pyogenes. In light of the emergence of methicillin-resistant S. aureus in the community and increasing resistance to mupirocin, REP8839 is being evaluated as a topical agent for the treatment of superficial skin infections. REP8839 was active against resistant phenotypes of S. aureus and can be formulated at high concentrations to minimize the development of resistance. A formulation of REP8839 has demonstrated efficacy in a porcine partial thickness wound infection model against mupirocin-resistant S. aureus.     

Anti-infection silver nanoparticle immobilized biomaterials facilitated by argon plasma grafting technology

Many research groups have attained slow, persistent, continuous release of silver ions through careful experimental design using existing methods. Such methods effectively kill planktonic bacteria and therefore prevent surface adhesion of pathogens. However, the resultant modified coatings cannot provide long-term antibacterial efficacy due to sustained anti-microbial release. In this study, the anti-infection activity of AgNP immobilized biomaterials was evaluated, facilitated by argon plasma grafting technology and activated by bacterial colonization. The modified materials generated in this study showed excellent specificity and were active against both Gram-positive and Gram-negative biofilm forming bacteria, including methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli. The anti-infection biomaterials developed in this study demonstrate several attractive advantages in comparison to traditional anti-bacterial surfaces loaded with antibiotics or other types of antibacterial agents and include (1) broad spectrum of activity against antibiotic resistant bacteria, (2) the unlikelihood of bacterial resistance, (3) specificity, (4) biocompatibility, and (5) stability.     

Design, synthesis and structure-activity relationship studies of novel indazole analogues as DNA gyrase inhibitors with Gram-positive antibacterial activity

In this study, we report the design, synthesis and structure-activity relationships of novel indazole derivatives as DNA gyrase inhibitors with Gram-positive antibacterial activity. Our results show that selected compounds from this series exhibit potent antibacterial activity against Gram-positive bacteria including multi-drug resistant strains that is methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE).     

Bactericidal properties of group IIA and group V phospholipases A2

Group V phospholipase A(2) (PLA(2)) is a recently characterized 14-kDa secretory PLA(2) of mammalian heart and macrophage-derived cells. Group IIA PLA(2), which is structurally close to group V PLA(2), has been shown to kill Gram-positive bacteria in vitro and to prevent symptoms of Gram-positive infection in vivo. We studied the antibacterial properties of fully active recombinant rat group IIA and V PLA(2)s. Both group IIA and V PLA(2)s were highly bactericidal against Gram-positive bacteria, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. Only high concentrations of group IIA PLA(2) showed some bactericidal effect against the Gram-negative bacterium Escherichia coli. Our results confirm that group IIA PLA(2) is a potent antibacterial enzyme against Gram-positive bacteria. Moreover, we show here that group V PLA(2) is a novel antibacterial mammalian protein, but is less potent than group IIA PLA(2). Both enzymes may be considered as future therapeutic agents against bacterial infections.     

The isolation, purification and biological activity of a novel antibacterial compound produced by Pseudomonas stutzeri

A novel compound designated zafrin [4beta-methyl-5, 6, 7, 8 tetrahydro-1 (4beta-H)-phenanthrenone] was isolated from a crude extract of a marine bacterium identified as Pseudomonas stutzeri. Zafrin showed strong antibacterial activity against both Gram-positive and Gram-negative bacteria. The compound was purified and its structure was elucidated by spectroscopic methods including 1H-nuclear magnetic resonance (NMR), 13C-NMR, 1D-NMR and 2D-NMR spectroscopy. It could be demonstrated that a purified solution of zafrin was active against several human pathogens, including Staphylococcus aureus, and Salmonella typhi. By contrast, zafrin did not inhibit the growth of eukaryotic organisms Candida albicans and Schizosaccharomyces pombe. The minimal inhibitory concentration for Gram-positive bacteria ranged from 50 to 75 microg mL(-1) and varied between 75 and 125 microg mL(-1) for Gram-negative bacteria. Zafrin lysed Bacillus subtilis cells grown in an osmotically protected medium, suggesting that it does not act upon the cell wall. Further investigation using B. subtilis indicated that the compound is bactericidal and is likely to target the cell membrane.     

New N-substituted 7-aminocephalosporanic acid derivatives as potential agents against Streptococcus pneumoniae. Synthesis and in vitro activity

The synthesis and the antimicrobial properties of a new series of cephalosporinic beta-lactam antibiotics is described. The data reported in the present paper show the potential of this type of substituted cephalosporins as new anti Gram-positive antibiotic drugs. In fact, all compounds tested showed a good in vitro antibacterial activity against the most relevant Gram-positive pathogens including resistant species that currently represent unmet medical need. On the contrary, the new synthesized compounds were found to be completely devoid of any activity on Gram-negative bacteria up to a concentration of the single agent of 128 microg/ml.     

Synthesis and antibacterial activity of new N-linked 5-triazolylmethyl oxazolidinones

A new series of N-linked 5-triazolylmethyl oxazolidinones with varying substitution at the piperazine nitrogen 4-position were synthesized and tested against a panel of Gram-positive and Gram-negative bacteria including clinical isolates. Most of the compounds showed excellent antibacterial activity against susceptible and resistant Gram-positive organisms. One of the compounds showed enhanced antibacterial activity against Moraxella catarrhalis.     

Structure-activity relationship study of anoplin.

Anoplin is a decapeptide amide, GLLKRIKTLL-NH2 derived from the venom sac of the solitary spider wasp, Anoplius samariensis. It is active against Gram-positive and Gram-negative bacteria and is not hemolytic towards human erythrocytes. The present paper reports a structure-activity study of anoplin based on 37 analogues including an Ala-scan, C- and N-truncations, and single and multiple residue substitutions with various amino acids. The analogues were tested for antibacterial activity against both S. aureus ATCC 25923 and E. coli ATCC 25922, and several potent antibacterial analogues were identified. The cytotoxicity of the analogues against human erythrocytes was assessed in a hemolytic activity assay. The antibacterial activity and selectivity of the analogues against S. aureus and E. coli varied considerably, depending on the hydrophobicity and position of the various substituted amino acids. In certain cases the selectivity for Gram-positive and Gram-negative bacteria was either reversed or altogether eliminated. In addition, it was generally found that antibacterial activity coincided with hemolytic activity.     

Investigation of antibiotic and antibacterial agent cross-resistance in target bacteria from homes of antibacterial product users and nonusers

AIM: To describe the relationship between antibiotic and antibacterial resistance in environmental and clinical bacteria from home environments across geographical locations, relative to the use or nonuse of antibacterial products, with a focus on target organisms recognized as potential human pathogens. METHODS AND RESULTS: In a randomized study, environmental and clinical samples were collected from the homes of antibacterial product users (n=30) and nonusers (n=30) for the isolation of target bacteria for antibiotic and antibacterial testing in three geographical areas (in USA and UK). Isolates were tested for antibiotic susceptibility, with selected antibiotic-resistant and antibiotic-susceptible isolates tested against four common antibacterial agents (triclosan, para-chloro-meta-xylenol, pine oil and quaternary ammonium compound). Prequalified users and nonusers at each location were randomly selected after meeting exclusionary criteria. Of 1238 isolates, more target bacteria were recovered from nonuser than user homes. Of Staphylococcus aureus isolates (n=33), none showed resistance to oxacillin or vancomycin; for Enterococcus sp. (n=149), none were resistant to ampicillin or vancomycin; and for Klebsiella pneumoniae (n=54)and Escherichia coli (n=24), none were resistant to third generation cephalosporins. Antibiotic resistance to one or more of the standard test panel drugs for Gram-positive and Gram-negative target bacteria was comparable between nonuser and user homes for both environmental and clinical isolates [e.g. resistance of environmental coagulase-negative (CN) Staphylococcus sp. was 73.8% (124/168) from nonuser homes and 73.0% (111/152) from user homes, and Enterobacteriaceae other than E. coli, 75.9% (186/245) from nonuser homes compared with 78.0% from user homes]. Of 524 Gram-negatives tested against preferred/alternative drugs, 97.1% (509/524) were susceptible to all antibiotics, across both groups. Isolates of S. aureus, Enterococcus sp. and CN Staphylococcus sp. susceptible to all preferred treatment drugs showed comparable antibacterial minimum inhibitory concentration (MIC) results between nonuser and user home isolates. For Gram-positives resistant to one or more preferred drugs, greatest resistance to antibacterial active ingredients was found in the nonuser group. For Gram-negatives, the antibacterial MIC data were comparable for isolates that were fully susceptible and resistant to one or more preferred/alternative treatment antibiotics. CONCLUSIONS: The results showed a lack of antibiotic and antibacterial agent cross-resistance in target bacteria from the homes of antibacterial product users and nonusers, as well as increased prevalence of potential pathogens in nonuser homes. SIGNIFICANCE AND IMPACT OF THE STUDY: It refutes widely publicized, yet unsupported, hypotheses that use of antibacterial products facilitates the development of antibiotic resistance in bacteria from the home environment.     

Commensal bacilli inhibitory to mastitis pathogens isolated from the udder microbiota of healthy cows

AIMS: To isolate from the microbiota of the healthy cow udder commensal bacteria having antimicrobial activity against bovine mastitis pathogens, with a long-term view to their potential application as antimastitis probiotics. METHODS AND RESULTS: Bacterial isolates from four healthy cow udders were tested for inhibitory activity against three Gram-positive indicator bacteria. This led to the selection of nine broadly inhibitory strains. All were of the Bacillus genus and their antimicrobial activities, which appeared heterogeneous on the basis of their antibacterial spectra and heat susceptibilities, enabled grouping of the inhibitory bacilli into six different inhibitory profiles. All displayed strong in vitro activity against Gram-positive mastitis pathogens. Inhibitory bacilli were recovered from each of the 11 udder samples collected over 7 months from one of these cows and the isolates included representatives of all six inhibitory profiles. CONCLUSIONS: Bacilli present in the udder microbiota of healthy cows can produce a variety of broadly active inhibitors of Gram-positive bacteria, including potential mastitis pathogens. SIGNIFICANCE AND IMPACT OF THE STUDY: Inhibitor-producing strains of commensal Bacillus species have been identified, which may have the potential for use as possible antimastitis probiotics.     

Antibacterial peptides isolated from insects.

Insects are amazingly resistant to bacterial infections. To combat pathogens, insects rely on cellular and humoral mechanisms, innate immunity being dominant in the latter category. Upon detection of bacteria, a complex genetic cascade is activated, which ultimately results in the synthesis of a battery of antibacterial peptides and their release into the haemolymph. The peptides are usually basic in character and are composed of 20-40 amino acid residues, although some smaller proteins are also included in the antimicrobial repertoire. While the proline-rich peptides and the glycine-rich peptides are predominantly active against Gram-negative strains, the defensins selectively kill Gram-positive bacteria and the cecropins are active against both types. The insect antibacterial peptides are very potent: their IC50 (50% of the bacterial growth inhibition) hovers in the submicromolar or low micromolar range. The majority of the peptides act through disintegrating the bacterial membrane or interfering with membrane assembly, with the exception of drosocin, apidaecin and pyrrhocoricin which appear to deactivate a bacterial protein in a stereospecific manner. In accordance with their biological function, the membrane-active peptides form ordered structures, e.g. alpha-helices or beta-pleated sheets and often cast permeable ion-pores. Their cytotoxic properties were exploited in in vivo studies targeting tumour progression. Although the native peptides degrade quickly in biological fluids other than insect haemolymph, structural modifications render the peptides resistant against proteases without sacrificing biological activity. Indeed, a pyrrhocoricin analogue shows lack of toxicity in vitro and in vivo and protects mice against experimental Escherichia coli infection. Careful selection of lead molecules based on the insect antibacterial peptides may extend their utility and produce viable alternatives to the conventional antimicrobial compounds for mammalian therapy.     

Antibacterial activities of mono-, di- and tri-substituted triphenylamine-based phosphonium ionic liquids

We report the synthesis of new mono, di and tri phosphonium ionic liquids and the evaluation of their antibacterial activities on both Gram-positive and Gram-negative bacteria from the ESKAPE-group. Among the molecules synthesized some of them reveal a strong bactericidal activity (MIC?=?0.5?mg/L) for Gram-positive bacteria (including resistant strains) comparable to that of standard antibiotics. A comparative Gram positive and Gram negative antibacterial activities shows that the nature of counter-ion has no significant effects. Interestingly, the increase of phosphonium lateral chains (from 4 to 8 carbons) results in a decrease of antibacterial activities. However, the increase of the spacer length has a positive influence on the activity on both Gram-positive and Gram-negative bacteria except for E. aerogenes. Finally, the increased charge density has no effect on the Gram-positive antibacterial activities (MIC between 2 and 4?mg/L) but seems to attenuate (except for P. aeruginosa) the discrimination between Gram-positive and Gram-negative. Overall these results suggest a unique mechanism of action of these triphenylamine-phosphonium ionic liquid derivatives.     

Synthesis and in vitro antibacterial activity of oxazolidine LBM-415 analogs as peptide deformylase inhibitors

The drug resistant bacteria pose a severe threat to human health. The increasing resistance of those pathogens to traditional antibacterial therapy renders the identification of new antibacterial agents with novel antibacterial mechanisms an urgent need. In this study, a series of (2S)-N-substituted-1-[(formyhydroxyamino)methyl]-1-oxohexyl]-2-oxazolidinecarboxamides were designed, synthesized and evaluated for in vitro antibacterial activity. Most of these compounds displayed good activities against Gram-positive organisms comparable to reference agent LBM-415.     

Taking inventory: antibacterial agents currently at or beyond phase 1

At least 18 antibacterial agents are currently undergoing clinical trials for the treatment of infections caused by susceptible and resistant bacteria. The beta-lactam class includes new parenteral carbapenems and cephalosporins with varying spectra of activities. The glycopeptides are antibiotics with in vitro activity primarily against Gram-positive bacteria, including multi-resistant strains. Three quinolones are being investigated for use against a variety of Gram-positive and respiratory Gram-negative organisms. Several other classes of antibacterial agents currently in clinical trials are represented by a glycolipodepsipeptide, a dihydrofolate reductase inhibitor, an oxazolidinone, two peptide antibiotics, a glycylcycline, and a peptide deformylase inhibitor, a member of a new antibacterial class.     

New fluorescent rosamine chelator showing promising antibacterial activity against Gram-positive bacteria

The restricted number of antibiotics to treat infections caused by common multidrug resistant bacterial pathogens in the clinical setting demands a continuous search for new molecules with antibacterial properties. Bacterial iron deprivation represents a promising alternative, being iron chelators an attractive class for drug design in which particular compounds seem to have antibacterial effect.In this work, we report the synthesis and characterization of a new fluorescent 3-hydroxy-4-pyridinone (3,4-HPO) iron chelator functionalized with a carboxyrosamine fluorophore (MRB20). The antibacterial activity of MRB20 was assessed against representative strains from clinically relevant Gram-positive and Gram-negative bacterial species and further compared with the inhibitory effect of a set of structurally related iron chelators including Deferiprone (1,2-dimethyl-3-hydroxy-4-pyridinone). Compounds exhibiting a promising minimal inhibitory concentration (MIC < 10 mg/L) were further tested against a wider range of bacterial genera and species (Staphylococcus spp. Enterococcus spp. Listeria monocytogenes, Bacillus spp.), including multidrug resistant bacteria.With the exception of the novel compound (MRB20), all chelators inhibited the strains assayed at very high concentrations [minimum inhibitory concentrations (MIC) ranging from 70 mg/L to >180 mg/L]. MRB20 revealed a good antibacterial activity (6.7–13.2 mg/L) against Gram-positive strains from different genera and species, including clinically relevant species (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Enterococcus faecalis), which might be eventually compatible with a therapeutic application or as adjuvant.     

Short cationic lipopeptides as effective antibacterial agents: Design,physicochemical properties and biological evaluation

The spread of drug-resistant bacteria has imparted a sense of urgency in the search for new antibiotics. In an effort to develop a new generation of antibacterial agents, we have designed de novo charged lipopeptides inspired by natural antimicrobial peptides. These short lipopeptides are composed of cationic lysine and hydrophobic lipoamino acids that replicate the amphiphilic properties of natural antimicrobial peptides. The resultant lipopeptides were found to self-assemble into nanoparticles. Some were effective against a variety of Gram-positive bacteria, including strains resistant to methicillin, daptomycin and/or vancomycin. The lipopeptides were not toxic to human kidney and liver cell lines and were highly resistant to tryptic degradation. Transmission electron microscopy analysis of bacteria cells treated with lipopeptide showed membrane-damage and lysis with extrusion of cytosolic contents. With such properties in mind, these lipopeptides have the potential to be developed as new antibacterial agents against drug-resistant Gram-positive bacteria.     

Synthesis and antibacterial activity of a novel series of acylides active against community acquired respiratory pathogens

A novel series of acylides 4 were designed to overcome antibacterial resistance and evaluated for in vitro and in vivo activity. This series of acylides was designed from clarithromycin by changing the substitution on the desosamine nitrogen, followed by conversion to 3-O-acyl and 11,12-carbamate. These compounds showed significantly potent antibacterial activity against not only Gram-positive pathogens, including macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens such as Haemophilus influenzae. These acylides also showed better activity against telithromycin resistant Streptococcus pneumoniae strains.     

Bactericidal Activity of Curcumin I Is Associated with Damaging of Bacterial Membrane

Curcumin, an important constituent of turmeric, is known for various biological activities, primarily due to its antioxidant mechanism. The present study focused on the antibacterial activity of curcumin I, a significant component of commercial curcumin, against four genera of bacteria, including those that are Gram-positive (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa). These represent prominent human pathogens, particularly in hospital settings. Our study shows the strong antibacterial potential of curcumin I against all the tested bacteria from Gram-positive as well as Gram-negative groups. The integrity of the bacterial membrane was checked using two differential permeabilization indicating fluorescent probes, namely, propidium iodide and calcein. Both the membrane permeabilization assays confirmed membrane leakage in Gram-negative and Gram-positive bacteria on exposure to curcumin I. In addition, scanning electron microscopy and fluorescence microscopy were employed to confirm the membrane damages in bacterial cells on exposure to curcumin I. The present study confirms the broad-spectrum antibacterial nature of curcumin I, and its membrane damaging property. Findings from this study could provide impetus for further research on curcumin I regarding its antibiotic potential against rapidly emerging bacterial pathogens.