Narrow Antibacterial Spectrum Research Articles

A ligand-based approach for enhancing the pharmacokinetic profile of highly charged antibacterial agents

Glutamate racemase catalyses the interconversion of l-glutamate and d-glutamate making available d-glutamate which is essential for peptidoglycan biosynthesis. Inhibitors of this enzyme have exhibited antibacterial activity with the d-glutamate-analogues group of inhibitors being the most significant as it is the only group that has demonstrated efficacy in a murine thigh Streptococcus pneumoniae infection model. This group of inhibitors, however, showed a narrow antibacterial spectrum that could be due to poor lipophilicity and permeability properties. Here, we have adopted a computational ligand-based drug design approach to enhance the lipophilicity and, hence, the antibacterial spectrum of this group of inhibitors. By limiting the charged groups on our pharmacophore model and identifying key interactions for glutamate racemase binding and inhibition, we have successfully searched a compound database for compounds with both antibacterial activity and increased lipophilicity. However, our compounds appear less potent, likely due to decreased specificity. We also demonstrate that permeability and lipophilicity alone are not responsible for the narrow antibacterial spectrum observed in the d-glutamate analogue inhibitors.

Development of Wide-Spectrum Hybrid Bacteriocins for Food Biopreservation

The food industry demands new procedures and methods to produce minimally processed, ready to eat food with intact nutritional, taste, and flavor properties. The biopreservation and the use of both bacteriocins produced by lactic acid bacteria (LAB) and bacteriocinogenic strains as an alternative to substitute chemical antimicrobial for food preservation became increasingly important in the last two decades. When the new proposed natural preservatives techniques are applied, probiotics food can be obtained and, simultaneously, foodborne pathogens and spoilage contaminants can diminish. However, bacteriocins produced by LAB have a narrow antibacterial spectrum and are inactive against Gram-negative bacteria like Salmonella and the emergent enterohemorrhagic Escherichia coli. Knowing the mechanism of action and the structural features of microcins synthesized by Gram-negative bacteria and with potent antimicrobial activity against the mentioned microorganism, the proposal is to obtain hybrid peptides (microcin–bacteriocin) with broad antimicrobial spectrum. This review explains how the inability of bacteriocins to cross the outer membrane of Gram-negative bacteria unable them to act on the bacteria. It will also be discussed how a hybrid bacteriocin can be obtained.

Synthesis of indolizine derivatives with selective antibacterial activity against Mycobacterium tuberculosis

1-Substituted indolizines with activity against Mycobacterium tuberculosis have been synthesized. The most active compounds carry an hydroxyphenylmethyl- or hydroxyalkyl substituent in the indolizine 1-position. The alkyl chain should be moderately long (C-5 or C-6). Aryl groups in the 2- and 3-position of the indolizine are also required. Removal of the 3-substituent resulted in significant loss of activity. A nitrile substituent in the 7-position is beneficial for both chemical stability and bioactivity. The compounds studied display a narrow antibacterial spectrum and appear to be quite selective antimycobacterial compounds. Moderate activity against certain pathogenic protozoa was also observed.

Antioxidant and antimicrobial activities of Morchella conica Pers.

Antioxidant capacity and antimicrobial activities of Morchella conica Pers. extracts obtained with ethanol were investigated in this study. Four complementary test systems; namely DPPH free radical scavenging, �-carotene/linoleic acid systems, total phenolic compounds and total flavonoid concentration were used. Inhibition values of M. conica ethanol extracts, buthylated hydroxyanisol (BHA) and �-tocopherol standards were found to be 96.9, 98.9 and 99.2%, respectively, at a concentration of 160 µg/ml. When compared the inhibition levels of methanol extract of M. conica and standards in linoleic acid system, it was observed that the higher the concentration of both M. conica ethanol extract and the standards the higher the inhibition effect. Total flavonoid amount was 9.17±0.56 µg mg -1 quercetin equivalent while the phenolic compound amount was 41.93±0.29 µg mg -1 pyrocatechol equivalent in the ethanolic extract. The antimicrobial effect of M. conica ethanol extract was tested against six species of Gram-positive bacteria, seven species of Gram-negative bacteria and one species of yeast. The M. conica ethanol extract had a narrow antibacterial spectrum against tested microorganisms. The most susceptible bacterium was M. flavus. The crude extract was found active on S. aureus ATCC 25923 and S. aureus Cowan I. The M. conica ethanol extract did not exhibit anticandidal activity against C. albicans.

Bacteriophage Endolysins as a Novel Class of Antibacterial Agents

Endolysins are double-stranded DNA bacteriophage-encoded peptidoglycan hydrolases produced in phage-infected bacterial cells toward the end of the lytic cycle. They reach the peptidoglycan through membrane lesions formed by holins and cleave it, thus, inducing lysis of the bacterial cell and enabling progeny virions to be released. Endolysins are also capable of degrading peptidoglycan when applied externally (as purified recombinant proteins) to the bacterial cell wall, which also results in a rapid lysis of the bacterial cell. The unique ability of endolysins to rapidly cleave peptidoglycan in a generally species-specific manner renders them promising potential antibacterial agents. Originally developed with a view to killing bacteria colonizing mucous membranes (with the first report published in 2001), endolysins also hold promise for the treatment of systemic infections. As potential antibacterials, endolysins possess several important features, for instance, a novel mode of action, a narrow antibacterial spectrum, activity against bacteria regardless of their antibiotic sensitivity, and a low probability of developing resistance. However, there is only one report directly comparing the activity of an endolysin with that of an antibiotic, and no general conclusions can be drawn regarding whether lysins are more effective than traditional antibiotics. The results of the first preclinical studies indicate that the most apparent potential problems associated with endolysin therapy (e.g., their immunogenicity, the release of proinflammatory components during bacteriolysis, or the development of resistance), in fact, may not seriously hinder their use. However, all data regarding the safety and therapeutic effectiveness of endolysins obtained from preclinical studies must be ultimately verified by clinical trials. This review discusses the prophylactic and therapeutic applications of endolysins, especially with respect to their potential use in human medicine. Additionally, we outline current knowledge regarding the structure and natural function of the enzymes in phage biology, including the most recent findings.

Synthesis and antibacterial properties of peptidyl derivatives and cyclopeptides structurally based upon the inhibitory centre of human cystatin C: Dissociation of antiproteolytic and antibacterial effects

Cysteine protease‐inhibiting proteins of the cystatin superfamily can inhibit the replication of certain viruses and bacteria. The inhibitory centre of human cystatin C, the most widely distributed human cystatin, comprises three peptide segments. The present work describes the synthesis and antibacterial activity of 27 new peptidyl derivatives or cyclopeptides based upon the aminoterminal segment Arg8‐Leu9‐Val10‐Gly11. Fourteen of the new compounds displayed antibacterial activity against from 1 up to 9 of 17 clinically important bacterial species tested. Antiproteolytic activity of a compound was usually not required for its antibacterial capacity. Peptidyl diazomethanes generally had a very narrow antibacterial spectrum, inhibiting only Streptococcus pyogenes, whereas cyclopeptides and peptidyl derivatives of the general structure X‐Arg‐Leu‐NH‐CH(iPr)‐CH2‐NH‐Y had a much wider spectrum. The most potent of these substances displayed approximately equal minimal inhibitory and bactericidal concentrations of about 20 μg/ml for both Staphylococcus aureus and S. pyogenes and were devoid of antiproteolytic activity. Several of the new substances could protect mice against lethal intraperitoneal challenge with S. pyogenes. Though their target remains to be disclosed, the group of substances here reported might be promising for the development of antibacterial drugs and the discovery of novel principles of action.

Synthesis and antibacterial properties of peptidyl derivatives and cyclopeptides structurally based upon the inhibitory centre of human cystatin C. Dissociation of antiproteolytic and antibacterial effects.

Cysteine protease-inhibiting proteins of the cystatin superfamily can inhibit the replication of certain viruses and bacteria. The inhibitory centre of human cystatin C, the most widely distributed human cystatin, comprises three peptide segments. The present work describes the synthesis and antibacterial activity of 27 new peptidyl derivatives or cyclopeptides based upon the aminoterminal segment Arg8-Leu9-Val10-Gly11. Fourteen of the new compounds displayed antibacterial activity against from 1 up to 9 of 17 clinically important bacterial species tested. Antiproteolytic activity of a compound was usually not required for its antibacterial capacity. Peptidyl diazomethanes generally had a very narrow antibacterial spectrum, inhibiting only Streptococcus pyogenes, whereas cyclopeptides and peptidyl derivatives of the general structure X-Arg-Leu-NH-CH(iPr)-CH2-NH-Y had a much wider spectrum. The most potent of these substances displayed approximately equal minimal inhibitory and bactericidal concentrations of about 20 microg/ml for both Staphylococcus aureus and S. pyogenes and were devoid of antiproteolytic activity. Several of the new substances could protect mice against lethal intraperitoneal challenge with S. pyogenes. Though their target remains to be disclosed, the group of substances here reported might be promising for the development of antibacterial drugs and the discovery of novel principles of action.

Mupirocin, fusidic acid and bacitracin: activity, action and clinical uses of three topical antibiotics.

Antibiotics applied to the skin must be formulated in a base that is nonirritant and nontoxic. They may have a narrow or fairly wide spectrum of activity but should produce no local reaction or sensitization; the commensal flora should not be affected unduly. Three antibiotics that have been used topically in humans and animals are fusidic acid, mupirocin and bacitracin, all of which have a narrow antibacterial spectrum. When applied to intact skin, fusidic acid penetrates more rapidly than other antibiotics. Clinically, the frequency of staphylococcal resistance to it and to mupirocin has remained low. Fusidic acid and mupirocin have been recommended for the treatment of acute staphylococcal skin lesions. However, the use of topical antibiotics for the treatment of chronic or recurring dermatitis and surgical or infected wounds may be inappropriate because of possible development of resistance and sensitization. Topical use of bacitracin may produce treatment failure and sensitization.

Identification and partial characterization of tochicin, a bacteriocin offduced by Bacillus thuringiensis subsp tochigiensis.

Bacillus thuringiensis subsp tochigiensis HD868 was identified as a bacteriocin producer which exhibited a bactericidal effect against closely related species. This bacteriocin designated as tochicin, was partially purified by 75% ammonium sulfate precipitation followed by subsequent dialysis. This partially purified tochicin showed a narrow antibacterial spectrum of activity against most of 20 typical B. thuringiensis strains and a strain of B. cereus, but not against other bacteria and yeasts tested. The antibacterial activity of tochicin on sensitive indicator cells disappeared completely by proteinase K treatment (1 mg ml-1), which indicates its proteinaceous nature. Tochicin was very stable throughout the range of pH 3.0-9.0 and was relatively heat-stable at 90 degrees C, but bacteriocin activity was not detected after boiling for 30 min. The relationship between cell growth and bacteriocin production was studied in a semi-defined medium. Tochicin activity was detected at the mid-log growth phase, reached the maximum at the early stationary phase, but decreased after the stationary phase. Direct detection of tochicin activity on sodium dodecyl sulfate-polyacrylamide gel suggested it has an apparent molecular mass of about 10.5 kDa. Tochicin exhibited a bactericidal activity against B. thuringiensis subsp thompsoni HD522 in phosphate buffer (pH 7.0).

Antibacterial Substances Produced byEnterococcus faecium

Two Enterococcus faecium isolated from silages produced antibacterial substances. Based on their narrow antibacterial spectrum, proteinaceous nature, and bactericidal mode of action, the antibacterial substances were concluded to be bacteriocins. Tricine–SDS–polyacrylamide gel electrophoresis and an electro-blotting-activity staining analysis indicated that both bacteriocins were peptides.

Antimicrobial activity of Polygonum equisetiforme extracts and flavonoids

AbstractMethanol, hexane, aqueous and petroleum ether extracts of the whole plant Polygonum equisetiforme did not show any activity against ten bacterial and four fungal species. The butanol crude extract and all the pooled groups of this exhibited variable patterns of antimicrobial activity. Quercetin (a flavonol) has been isolated and identified as the major constituent. The antifungal and antibacterial activity of quercetin was compared with the antibacterial drugs gentamycin, streptomycin and ampicillin and the antifungal drug miconazole nitrate. The antifungal activity of quercetin was limited to Candida tropicalis and it had a narrow antibacterial spectrum of activity. However, its activities against Enterobacter aerogenes and Escherichia coli were low grade compared with ampicillin, stretomycin and gentamycin. Quercetin‐3‐O‐rhamnoside, quercetin‐3‐O‐glucuronide, quercetin‐3‐O‐arabinoside and isorhamnetin were also isolated in very low yield. They have not been reported previously in this species.

Bacteriocin-Producing Strain of Lactococcus lactis subsp. diacitilactis S50

Lactococcus lactis subsp. diacitilactis S50 produces a bacteriocin, designated bacteriocin S50, which has a narrow antibacterial spectrum. It was active only against Lactococcus species, including a nisin producer exhibiting a bactericidal effect. The activity of bacteriocin S50 was sensitive to proteases. It retained antimicrobial activity after being heated to 100 degrees C for up to 60 min and in the pH range 2 to 11.

LL-E19020 alpha and beta, animal growth promoting antibiotics: taxonomy, fermentation and biological activity.

Antibacterial antibiotics LL-E19020 alpha and beta were isolated from the fermentation broth of an actinomycete strain. Based on cultural and physiological characteristics, culture LL-E19020 was identified as a new subspecies of Streptomyces lydicus. The LL-E19020 alpha and beta antibiotics were found to possess a very narrow antibacterial spectrum against human pathogens. In studies in chickens, LL-E19020 alpha demonstrated excellent growth promoting activity.

Pharmacokinetics of phenoxymethyl penicillin (penicillin V) in calves.

Phenoxymethyl penicillin (penicillin V) was administered intravenously (i.v.) and orally to pre-ruminant calves and the distribution and elimination kinetics, as well as the oral bioavailability, were determined. After i.v. injection, the drug was distributed rapidly in the body, the elimination half-life (t1/2 beta) was 34 min and the apparent volume of distribution at steady-state (Vd ss) was 0.30 l/kg. Mean peak serum drug concentrations were directly related to the oral dose administered, i.e. 0.22 microgram/ml, 1.06 micrograms/ml and 2.14 micrograms/ml after dosing at 10, 20 and 40 mg/kg, respectively. The elimination t1/2 of the drug after oral dosing varied between 90 and 110 min, and the oral bioavailability was approximately 30% of the dose. The co-administration of phenoxymethyl penicillin and probenecid resulted in elevation and prolongation of serum drug concentration. The percentage of drug bound to serum proteins was 78.8% +/- 8.2%. Phenoxymethyl penicillin was probably inactivated and degraded in the gastrointestinal tract of 6-week-old calves fed exclusively hay, silage and concentrates as very low and erratic serum drug concentrations were measured after these calves were dosed orally with the drug at 40 mg/kg. In view of the narrow antibacterial spectrum of the drug and the relatively high dose required, it appears that phenoxymethyl penicillin can only be of limited practical value for the treatment of bacterial infections in preruminant calves.

The penetration of macrolides into bronchial secretions.

Macrolides have shown efficacy in the treatment of a large range of respiratory infections. These antibiotics are well tolerated, have a narrow antibacterial spectrum, and excellent diffusion properties. We have studied the penetration into bronchial secretions of three macrolides, erythromycin, josamycin and oleandomycin. The bronchial concentrations of erythromycin reached an average of 1 mg/l 2 h after oral administration of 1 g; they were lower for josamycin (0.52 mg/l) but the ratio between bronchial and simultaneous serum concentrations was similar for both drugs. Bronchial levels of oleandomycin were rapidly higher than the serum levels, reaching 3 to 4 mg/l, a ratio of more than 100%. Other studies on tissue concentrations of erythromycin and josamycin showed local levels of 4 to 6 mg/l, whereas in bronchial secretions the concentrations were identical to those measured in our study. On the whole, the good diffusion of macrolides into respiratory tissues and secretions as well as in-vitro antibacterial activity against most species responsible for respiratory infections confirm their indication in the treatment of these infections.

Chemical and biological characterization of a gonococcal growth inhibitor produced by Staphylococcus haemolyticus isolated from urogenital flora.

The purified antigonococcal substance produced by Staphylococcus haemolyticus no. 7 has shown a broad antigonococcal spectrum and a narrow antibacterial spectrum. The inhibitor produced in vitro was also active in the guinea pig subcutaneous chamber. The inhibitor has shown hemolytic activity; the human, horse, and mouse erythrocytes were the most susceptible. Hemolytic and antigonococcal activities were inhibited in the presence of phosphatidylcholine. The amino acid composition of the antigonococcal substance was characterized by the absence of proline, tyrosine, histidine, cysteine, and tryptophan. The molecular weight was found to be 2,565, and the major isoelectric points were 4.8 and 4.9 in the presence of 8 M urea and 4.6 without urea. The inhibitor has some properties similar to those of the delta toxin of Staphylococcus aureus, although the two substances are different based mainly on their chemical characteristics. Also an antiserum directed against the gonococcal inhibitor did not give a precipitation line with the delta toxin, indicating that the two substances are antigenically unrelated.

R-(Z)]-4-amino-3-chloro-2-pentenedioic acid, a new antibiotic. Fermentation, isolation and characterization.

A new unsaturated glutamic acid analog, 4-amino-3-chloro-2-pentenedioic acid ( ACPA ) was isolated from a fermentation broth produced by a strain of Streptomyces. ACPA has a very narrow antibacterial spectrum, which is virtually limited to Micrococcus luteus.

The management of endophthalmitis following cataract extraction.

Intraocular infection is perhaps the most dreaded of all the complications which may follow cataract extraction. When endophthalmitis is associated with a vitreous abscess, the chances of a successful end-result becomes very poor indeed. The introduction of modern chemotherapeutic and antibiotic agents has somewhat improved the outlook in these conditions in recent years, but intraocular infection has not yet become a complication to be viewed with equanimity. <h3>Clinical and Experimental Observations</h3> Between 1944 and 1948 occasional reports were published of the successful management of endophthalmitis by the sulfonamides and penicillin.^1-4The successes, however, were few, and the outlook was not hopeful. The sulfonamides apparently penetrate the blood-aqueous barrier satisfactorily, but their narrow antibacterial spectrum limits their field of usefulness. In 1944, von Sallmann and Meyer⁵demonstrated that penicillin, even when given systemically in massive doses, does not penetrate sufficiently into the vitreous to produce concentrations adequate to control