scholarly journals TSPphg Lysin from the Extremophilic Thermus Bacteriophage TSP4 as a Potential Antimicrobial Agent against Both Gram-Negative and Gram-Positive Pathogenic Bacteria

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 192 ◽  
Author(s):  
Feng Wang ◽  
Xinyu Ji ◽  
Qiupeng Li ◽  
Guanling Zhang ◽  
Jiani Peng ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Infection Model ◽  
Bacterial Cells ◽  
Skin Damage ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Gram Negative

New strategies against antibiotic-resistant bacterial pathogens are urgently needed but are not within reach. Here, we present in vitro and in vivo antimicrobial activity of TSPphg, a novel phage lysin identified from extremophilic Thermus phage TSP4 by sequencing its whole genome. By breaking down the bacterial cells, TSPphg is able to cause bacteria destruction and has shown bactericidal activity against both Gram-negative and Gram-positive pathogenic bacteria, especially antibiotic-resistant strains of Klebsiella pneumoniae, in which the complete elimination and highest reduction in bacterial counts by greater than 6 logs were observed upon 50 μg/mL TSPphg treatment at 37 °C for 1 h. A murine skin infection model further confirmed the in vivo efficacy of TSPphg in removing a highly dangerous and multidrug-resistant Staphylococcus aureus from skin damage and in accelerating wound closure. Together, our findings may offer a therapeutic alternative to help fight bacterial infections in the current age of mounting antibiotic resistance, and to shed light on bacteriophage-based strategies to develop novel anti-infectives.

scholarly journals In vitro and in vivo antibacterial efficacies of CFC-222, a new fluoroquinolone.

1997 ◽  
Vol 41 (10) ◽  
pp. 2209-2213 ◽  
Author(s):  
J H Kim ◽  
J A Kang ◽  
Y G Kim ◽  
J W Kim ◽  
J H Lee ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Protective Efficacy ◽  
Horse Serum ◽  
The Other ◽  
Infection Model ◽  
Gram Positive ◽  
Gram Negative ◽  
E Coli

CFC-222 is a novel fluoroquinolone containing a C-7 bicyclic amine moiety with potent antibacterial activities against gram-positive, gram-negative, and anaerobic organisms. We compared the in vitro and in vivo activities of CFC-222 with those of ciprofloxacin, ofloxacin, and lomefloxacin. CFC-222 was more active than the other fluoroquinolones tested against gram-positive bacteria. CFC-222 was particularly active against Streptococcus pneumoniae (MIC at which 90% of isolates are inhibited [MIC90], 0.2 microg/ml), Staphylococcus aureus (MIC90, 0.2 microg/ml for ciprofloxacin-susceptible strains), and Enterococcus faecalis (MIC90, 0.39 microg/ml). Against Escherichia coli and other members of the family Enterobacteriaceae, CFC-222 was slightly less active than ciprofloxacin (MIC90s for E. coli, 0.1 and 0.025 microg/ml, respectively). The in vitro activity of CFC-222 was not influenced by inoculum size, medium composition, or the presence of horse serum. However, its activity was decreased significantly by a change in the pH of the medium from 7.0 to 6.0, as was the case for the other quinolones tested. The in vivo protective efficacy of CFC-222 by oral administration was greater than those of the other quinolones tested in a mouse model of intraperitoneally inoculated systemic infection caused by S. aureus. CFC-222 exhibited efficacy comparable to that of ciprofloxacin in the same model of infection caused by gram-negative organisms, such as E. coli and Klebsiella pneumoniae. In this infection model, CFC-222 was slightly less active than ciprofloxacin against Pseudomonas aeruginosa. These results suggest that CFC-222 may be a promising therapeutic agent in various bacterial infections.

scholarly journals Novel Broad-Spectrum Bis-(Imidazolinylindole) Derivatives with Potent Antibacterial Activities against Antibiotic-Resistant Strains

2009 ◽  
Vol 53 (10) ◽  
pp. 4283-4291 ◽  
Author(s):  
Rekha G. Panchal ◽  
Ricky L. Ulrich ◽  
Douglas Lane ◽  
Michelle M. Butler ◽  
Chad Houseweart ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Bacterial Species ◽  
In Vivo Studies ◽  
Structural Variations ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Resistant Strains

ABSTRACT Given the limited number of structural classes of clinically available antimicrobial drugs, the discovery of antibacterials with novel chemical scaffolds is an important strategy in the development of effective therapeutics for both naturally occurring and engineered resistant strains of pathogenic bacteria. In this study, several diarylamidine derivatives were evaluated for their ability to protect macrophages from cell death following infection with Bacillus anthracis, a gram-positive spore-forming bacterium. Four bis-(imidazolinylindole) compounds were identified with potent antibacterial activity as measured by the protection of macrophages and by the inhibition of bacterial growth in vitro. These compounds were effective against a broad range of gram-positive and gram-negative bacterial species, including several antibiotic-resistant strains. Minor structural variations among the four compounds correlated with differences in their effects on bacterial macromolecular synthesis and mechanisms of resistance. In vivo studies revealed protection by two of the compounds of mice lethally infected with B. anthracis, Staphylococcus aureus, or Yersinia pestis. Taken together, these results indicate that the bis-(imidazolinylindole) compounds represent a new chemotype for the development of therapeutics for both gram-positive and gram-negative bacterial species as well as against antibiotic-resistant infections.

scholarly journals THE PRODUCTION OF BACTERICIDAL SUBSTANCES BY AEROBIC SPORULATING BACILLI

1941 ◽  
Vol 73 (5) ◽  
pp. 629-640 ◽  
Author(s):  
René J. Dubos ◽  
Rollin D. Hotchkiss
Keyword(s):  
Insoluble Fraction ◽  
Physiological Effect ◽  
Antagonistic Activity ◽  
Bacterial Cells ◽  
Animal Tissues ◽  
Gram Positive ◽  
Culture Collections ◽  
Gram Negative

Several species of aerobic sporulating bacilli recently isolated from soil, sewage, manure, and cheese, as well as authentic strains obtained from type culture collections, have been found to exhibit antagonistic activity against unrelated microorganisms. Cultures of these aerobic sporulating bacilli yield an alcohol-soluble, water-insoluble fraction,—tyrothricin,—which is bactericidal for most Gram-positive and Gram-negative microbial species. Two different crystalline products have been separated from tyrothricin. One, which may be called tyrocidine, is bactericidal in vitro for both Gram-positive and Gram-negative species; the other substance, gramicidin, is effective only against Gram-positive microorganisms. In general, tyrocidine behaves like a protoplasmic poison and like other antiseptics, loses much of its activity in the presence of animal tissues. Gramicidin on the contrary exerts a much more subtle physiological effect on the susceptible bacterial cells and, when applied locally at the site of the infection, retains in vivo a striking activity against Gram-positive microorganisms.

scholarly journals In Vitro and In Vivo Antibacterial Activities of Heteroaryl Isothiazolones against Resistant Gram-Positive Pathogens

2007 ◽  
Vol 51 (4) ◽  
pp. 1259-1267 ◽  
Author(s):  
Michael J. Pucci ◽  
Jijun Cheng ◽  
Steven D. Podos ◽  
Christy L. Thoma ◽  
Jane A. Thanassi ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Standard Dose ◽  
Antibacterial Activities ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACT The activities of several tricyclic heteroaryl isothiazolones (HITZs) against an assortment of gram-positive and gram-negative clinical isolates were assessed. These compounds target bacterial DNA replication and were found to possess broad-spectrum activities especially against gram-positive strains, including antibiotic-resistant staphylococci and streptococci. These included methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-nonsusceptible staphylococci, and quinolone-resistant strains. The HITZs were more active than the comparator antimicrobials in most cases. For gram-negative bacteria, the tested compounds were less active against members of the family Enterobacteriaceae but showed exceptional potencies against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria spp. Good activity against several anaerobes, as well as Legionella pneumophila and Mycoplasma pneumoniae, was also observed. Excellent bactericidal activity against staphylococci was observed in time-kill assays, with an approximately 3-log drop in the numbers of CFU/ml occurring after 4 h of exposure to compound. Postantibiotic effects (PAEs) of 2.0 and 1.7 h for methicillin-susceptible S. aureus and MRSA strains, respectively, were observed, and these were similar to those seen with moxifloxacin at 10× MIC. In vivo efficacy was demonstrated in murine infections by using sepsis and thigh infection models. The 50% protective doses were ≤1 mg/kg of body weight against S. aureus in the sepsis model, while decreases in the numbers of CFU per thigh equal to or greater than those detected in animals treated with a standard dose of vancomycin were seen in the animals with thigh infections. Pharmacokinetic analyses of treated mice indicated exposures similar to those to ciprofloxacin at equivalent dose levels. These promising initial data suggest further study on the use of the HITZs as antibacterial agents.

scholarly journals Antibacterial Efficacy of EravacyclineIn Vivoagainst Gram-Positive and Gram-Negative Organisms

2016 ◽  
Vol 60 (8) ◽  
pp. 5001-5005 ◽  
Author(s):  
Marguerite L. Monogue ◽  
Abrar K. Thabit ◽  
Yukihiro Hamada ◽  
David P. Nicolau
Keyword(s):  
Cumulative Dose ◽  
Dose Response ◽  
Bacterial Count ◽  
Infection Model ◽  
Gram Positive ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Content Type

ABSTRACTMembers of the tetracycline class are frequently classified as bacteriostatic. However, recent findings have demonstrated an improved antibacterial killing profile, often achieving ≥3 log10bacterial count reduction, when such antibiotics have been given for periods longer than 24 h. We aimed to study this effect with eravacycline, a novel fluorocycline, given in an immunocompetent murine thigh infection model over 72 h against two methicillin-resistantStaphylococcus aureus(MRSA) isolates (eravacycline MICs = 0.03 and 0.25 μg/ml) and threeEnterobacteriaceaeisolates (eravacycline MICs = 0.125 to 0.25 μg/ml). A humanized eravacycline regimen, 2.5 mg/kg of body weight given intravenously (i.v.) every 12 h (q12h), demonstrated progressively enhanced activity over the 72-h study period. A cumulative dose response in which bacterial density was reduced by more than 3 log10CFU at 72 h was noted over the study period in the two Gram-positive isolates, and eravacycline performed similarly to comparator antibiotics (tigecycline, linezolid, and vancomycin). A cumulative dose response with eravacycline and comparators (tigecycline and meropenem) over the study period was also observed in the Gram-negative isolates, although more variability in bacterial killing was observed for all antibacterial agents. Overall, a bacterial count reduction of ≥3 log was achieved in one of the three isolates with both eravacycline and tigecycline, while meropenem achieved a similar endpoint against two of the three isolates. Bactericidal activity is typically definedin vitroover 24 h; however, extended regimen studiesin vivomay demonstrate an improved correlation with clinical outcomes by better identification of antimicrobial effects.

Efficient Synthesis and Antibacterial Profile of Bis(2-hydroxynaphthalene- 1,4-dione)

2020 ◽  
Vol 20 (2) ◽  
pp. 121-131 ◽  
Author(s):  
Juliana S. Novais ◽  
Aline C. Rosandiski ◽  
Carolina M. de Carvalho ◽  
Letícia S. de Saules Silva ◽  
Lais C. dos S. Velasco de Souza ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Public Health Problem ◽  
In Vitro Toxicity ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Healthy Human ◽  
Gram Negative ◽  
Methicillin Resistant

Background: Antibacterial resistance is a serious public health problem infecting millions in the global population. Currently, there are few antimicrobials on the market against resistant bacterial infections. Therefore, there is an urgent need for new therapeutic options against these strains. Objective: In this study, we synthesized and evaluated ten Bis(2-hydroxynaphthalene-1,4-dione) against Gram-positive strains, including a hospital Methicillin-resistant (MRSA), and Gram-negative strains. Method: The compounds were prepared by condensation of aldehydes and lawsone in the presence of different L-aminoacids as catalysts in very good yields. The compounds were submitted to antibacterial analysis through disk diffusion and Minimal Inhibitory Concentration (MIC) assays. Result: L-aminoacids have been shown to be efficient catalysts in the preparation of Bis(2- hydroxynaphthalene-1,4-dione) from 2-hydroxy-1,4-naphthoquinones and arylaldehydes in excellent yields of up to 96%. The evaluation of the antibacterial profile against Gram-positive strains (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228) also including a hospital Methicillin-resistant S. aureus (MRSA) and Gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Klebsiella pneumoniae ATCC 4352), revealed that seven compounds showed antibacterial activity within the Clinical and Laboratory Standards Institute (CLSI) levels mainly against P. aeruginosa ATCC 27853 (MIC 8-128 µg/mL) and MRSA (MIC 32-128 µg/mL). In addition, the in vitro toxicity showed all derivatives with no hemolytic effects on healthy human erythrocytes. Furthermore, the derivatives showed satisfactory theoretical absorption, distribution, metabolism, excretion, toxicity (ADMET) parameters, and a similar profile to antibiotics currently in use. Finally, the in silico evaluation pointed to a structure-activity relationship related to lipophilicity for these compounds. This feature may help them in acting against Gram-negative strains, which present a rich lipid cell wall selective for several antibiotics. Conclusion: Our data showed the potential of this series for exploring new and more effective antibacterial activities in vivo against other resistant bacteria.

scholarly journals CD137 Expressed on Neutrophils Plays Dual Roles in Antibacterial Responses against Gram-Positive and Gram-Negative Bacterial Infections

2013 ◽  
Vol 81 (6) ◽  
pp. 2168-2177 ◽  
Author(s):  
Quang-Tam Nguyen ◽  
Thu-Ha T. Nguyen ◽  
Seong-A. Ju ◽  
Yea-Sol Lee ◽  
Seung Hyun Han ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Costimulatory Molecule ◽  
Host Responses ◽  
Gram Positive ◽  
Necrosis Factor Alpha ◽  
Gram Negative ◽  
Content Type ◽  
Stimulation Of

ABSTRACTSevere sepsis and septic shock caused mainly by bacterial infections are life-threatening conditions that urge the development of novel therapies. However, host responses to and pathophysiology of sepsis have not been clearly understood, which remains a major obstacle for the development of effective therapeutics. Recently, we have shown that stimulation of a costimulatory molecule, CD137, enhanced survival of mice infected with the Gram-positive (G+) intracellular bacteriumListeria monocytogenesbut decreased survival in a polymicrobial sepsis model. Herein, we report that CD137 deficiency or blocking of CD137 signaling decreased antibacterial responses of mice infected with G+bacteria (Staphylococcus aureus,Streptococcus pneumoniae, andEnterococcus faecalis) but increased these responses in mice infected with Gram-negative (G−) bacteria (Escherichia coli,Pseudomonas aeruginosa, andSalmonella entericaserovar Typhimurium). Consistent with these findings, stimulation of CD137 by administration of agonistic antibody enhanced responses against G+bacteria, whereas it decreased these responses against G−bacteria. Neutrophils were responsible for CD137-mediated opposite roles in control of G+and G−bacterial infections. Stimulation of CD137 enhanced activities of neutrophils againstS. aureusbut decreased these activities againstE. coli, while CD137 blocking produced opposite results with the stimulation of CD137in vivoandin vitro. Furthermore, we found that combined signaling of CD137 and Toll-like receptor 2 (TLR2) induced synergistic production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) by neutrophils, but combined signaling of CD137 and TLR4 did not. Our data strongly suggest that CD137 may play a dual role in sepsis in association with TLRs.

scholarly journals In Vitro and In Vivo Antibacterial Activities of CS-023 (RO4908463), a Novel Parenteral Carbapenem

2005 ◽  
Vol 49 (8) ◽  
pp. 3239-3250 ◽  
Author(s):  
Tetsufumi Koga ◽  
Tomomi Abe ◽  
Harumi Inoue ◽  
Takashi Takenouchi ◽  
Akiko Kitayama ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Systemic Infection ◽  
Antibacterial Activities ◽  
Infection Model ◽  
Gram Positive ◽  
Methicillin Resistant ◽  
Lung Infections ◽  
Systemic Infections

ABSTRACT CS-023 (RO4908463, formerly R-115685) is a novel 1β-methylcarbapenem with 5-substituted pyrrolidin-3-ylthio groups, including an amidine moiety at the C-2 position. Its antibacterial activity was tested against 1,214 clinical isolates of 32 species and was compared with those of imipenem, meropenem, ceftazidime, ceftriaxone, ampicillin, amikacin, and levofloxacin. CS-023 exhibited a broad spectrum of activity against gram-positive and -negative aerobes and anaerobes, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae (PRSP), β-lactamase-negative ampicillin-resistant Haemophilus influenzae, and Pseudomonas aeruginosa. CS-023 showed the most potent activity among the compounds tested against P. aeruginosa and MRSA, with MICs at which 90% of isolates tested were inhibited of 4 μg/ml and 8 μg/ml, respectively. CS-023 was stable against hydrolysis by the β-lactamases from Enterobacter cloacae and Proteus vulgaris. CS-023 also showed potent activity against extended-spectrum β-lactamase-producing Escherichia coli. The in vivo efficacy of CS-023 was evaluated with a murine systemic infection model induced by 13 strains of gram-positive and -negative pathogens and a lung infection model induced by 2 strains of PRSP (serotypes 6 and 19). Against the systemic infections with PRSP, MRSA, and P. aeruginosa and the lung infections, the efficacy of CS-023 was comparable to those of imipenem/cilastatin and vancomycin (tested against lung infections only) and superior to those of meropenem, ceftriaxone, and ceftazidime (tested against P. aeruginosa infections only). These results suggest that CS-023 has potential for the treatment of nosocomial bacterial infections by gram-positive and -negative pathogens, including MRSA and P. aeruginosa.

scholarly journals In VitroandIn VivoActivities of Novel, Semisynthetic Thiopeptide Inhibitors of Bacterial Elongation Factor Tu

2011 ◽  
Vol 55 (11) ◽  
pp. 5277-5283 ◽  
Author(s):  
J. A. Leeds ◽  
M. J. LaMarche ◽  
J. T. Brewer ◽  
S. M. Bushell ◽  
G. Deng ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Elongation Factor ◽  
Infection Model ◽  
Elongation Factor Tu ◽  
Bacterial Protein ◽  
Preclinical Development ◽  
Gram Positive ◽  
Content Type

ABSTRACTRecently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here thein vitroandin vivoactivities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistantStaphylococcus aureusand vancomycin-resistant enterococci (MIC90≤ 0.25 μg/ml) but weaker against the streptococci (MIC90≥ 4 μg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in thetufgene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethalS. aureusinfections with 50% effective doses (ED50) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemicE. faecalisinfections with ED50of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are activein vitroandin vivoactivity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy.

scholarly journals In Vitro and In Vivo Activities of Novel 2-(Thiazol-2-ylthio)-1β-Methylcarbapenems with Potent Activities against Multiresistant Gram-Positive Bacteria

2003 ◽  
Vol 47 (8) ◽  
pp. 2471-2480 ◽  
Author(s):  
Yutaka Ueda ◽  
Makoto Sunagawa
Keyword(s):  
Bactericidal Activity ◽  
Bacterial Infections ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Log Reduction ◽  
Highly Active ◽  
Time Kill

ABSTRACT SM-197436, SM-232721, and SM-232724 are new 1β-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In agar dilution susceptibility testing these novel carbapenems were active against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) with a MIC90 of ≤4 μg/ml. Furthermore, SM-232724 showed strong bactericidal activity against MRSA, in contrast to linezolid, which was bacteriostatic up to four times the MIC. SM-232724 showed good therapeutic efficacy comparable to those of vancomycin and linezolid against systemic infections of MRSA in cyclophosphamide-treated mice. The MICs of SM-197436, SM-232721, and SM-232724 for streptococci, including penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae strains, ranged from ≤0.063 to 0.5 μg/ml. These drugs were the most active β-lactams tested against Enterococcus faecium, and the MIC90 s for ampicillin-resistant E. faecium ranged between 8 and 16 μg/ml, which were slightly higher than the value for linezolid. However, time-kill assays revealed the superior bactericidal activity of SM-232724 compared to those of quinupristin-dalfopristin and linezolid against an E. faecium strain with a 4-log reduction in CFU at four times the MIC after 24 h of exposure to antibiotics. In addition, SM-232724 significantly reduced the numbers of bacteria in a murine abscess model with the E. faecium strain: its efficacy was superior to that of linezolid, although the MICs (2 μg/ml) of these two agents are the same. Among gram-negative bacteria, these three carbapenems were highly active against Haemophilus influenzae (including ampicillin-resistant strains), Moraxella catarrhalis, and Bacteroides fragilis, and showed antibacterial activity equivalent to that of imipenem for Escherichia coli, Klebsiella pneumoniae, and Proteus spp. Thus, these new carbapenems are promising candidates for agents to treat nosocomial bacterial infections by gram-positive and gram-negative bacteria, especially multiresistant gram-positive cocci, including MRSA and vancomycin-resistant enterococci.

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