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

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.

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

Viruses ◽

10.3390/v12020192 ◽

2020 ◽

Vol 12 (2) ◽

pp. 192 ◽

Cited By ~ 6

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.10.2209 ◽

1997 ◽

Vol 41 (10) ◽

pp. 2209-2213 ◽

Cited By ~ 12

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.

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Multiple Mechanisms of the Synthesized Antimicrobial Peptide TS against Gram-Negative Bacteria for High Efficacy Antibacterial Action In Vivo

Molecules ◽

10.3390/molecules26010060 ◽

2020 ◽

Vol 26 (1) ◽

pp. 60

Author(s):

Rui Zhang ◽

Xiaobo Fan ◽

Xinglu Jiang ◽

Mingyuan Zou ◽

Han Xiao ◽

...

Keyword(s):

Antimicrobial Peptide ◽

Bacterial Infections ◽

Bacterial Resistance ◽

Divalent Cations ◽

Resistant Bacteria ◽

Antibacterial Drug ◽

Gram Negative Bacteria ◽

Gram Negative

The emergence of drug-resistant bacteria emphasizes the urgent need for novel antibiotics. The antimicrobial peptide TS shows extensive antibacterial activity in vitro and in vivo, especially in gram-negative bacteria; however, its antibacterial mechanism is unclear. Here, we find that TS without hemolytic activity disrupts the integrity of the outer bacterial cell membrane by displacing divalent cations and competitively binding lipopolysaccharides. In addition, the antimicrobial peptide TS can inhibit and kill E. coli by disintegrating the bacteria from within by interacting with bacterial DNA. Thus, antimicrobial peptide TS’s multiple antibacterial mechanisms may not easily induce bacterial resistance, suggesting use as an antibacterial drug to be for combating bacterial infections in the future.

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

Infection and Immunity ◽

10.1128/iai.00115-13 ◽

2013 ◽

Vol 81 (6) ◽

pp. 2168-2177 ◽

Cited By ~ 8

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.8.3239-3250.2005 ◽

2005 ◽

Vol 49 (8) ◽

pp. 3239-3250 ◽

Cited By ~ 42

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.

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Inhibition of Multidrug-Resistant Gram-Positive and Gram-Negative Bacteria by a Photoactivated Porphyrin

Polish Journal of Microbiology ◽

10.5604/01.3001.0010.7092 ◽

2017 ◽

Vol 66 (4) ◽

pp. 533-536 ◽

Cited By ~ 2

Author(s):

Moreno Bondi ◽

Anna Mazzini ◽

Simona de Niederhäusern ◽

Ramona Iseppi ◽

Patrizia Messi

Keyword(s):

Multidrug Resistant ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Multidrug Resistant Bacteria ◽

Gram Positive ◽

Gram Negative ◽

E Coli ◽

In Vitro Antibacterial Activity

The authors studied the in vitro antibacterial activity of the photo-activated porphyrin meso-tri(N-methyl-pyridyl), mono(N-tetradecyl-pyridyl)porphine (C14) against four multidrug-resistant bacteria: Staphylococcus aureus, Enterococcus faecalis (Gram-positive), Escherichia coli, Pseudomonas aeruginosa (Gram-negative). Using 10 μg/ml of porphyrin and 60 sec irradiation we observed the remarkable susceptibility of S. aureus and E. faecalis to treatment while, under the same conditions, E. coli and P. aeruginosa showed very low susceptibility. In a later stage, suspensions of Gram-negative bacteria were processed with EDTA before photo-activation, obtaining a significant decrease in viable counts. In view of the results, if the combination of low porphyrin concentrations and short irradiation times will be effective in vivo also, this approach could be a possible alternative to antibiotics, in particular against localized infections due to multidrug-resistant microorganisms.

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Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents

International Journal of Molecular Sciences ◽

10.3390/ijms21186789 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6789

Author(s):

Tsz Tin Yu ◽

Rajesh Kuppusamy ◽

Muhammad Yasir ◽

Md. Musfizur Hassan ◽

Amani Alghalayini ◽

...

Keyword(s):

Antibacterial Activity ◽

Quaternary Ammonium ◽

Lipid Membranes ◽

Bacterial Infections ◽

Biological Evaluation ◽

In Vitro Toxicity ◽

Ammonium Iodide ◽

Gram Positive ◽

Gram Negative

There has been an increasing interest in the development of antimicrobial peptides (AMPs) and their synthetic mimics as a novel class of antibiotics to overcome the rapid emergence of antibiotic resistance. Recently, phenylglyoxamide-based small molecular AMP mimics have been identified as potential leads to treat bacterial infections. In this study, a new series of biphenylglyoxamide-based small molecular AMP mimics were synthesised from the ring-opening reaction of N-sulfonylisatin bearing a biphenyl backbone with a diamine, followed by the conversion into tertiary ammonium chloride, quaternary ammonium iodide and guanidinium hydrochloride salts. Structure–activity relationship studies of the analogues identified the octanesulfonyl group as being essential for both Gram-positive and Gram-negative antibacterial activity, while the biphenyl backbone was important for Gram-negative antibacterial activity. The most potent analogue was identified to be chloro-substituted quaternary ammonium iodide salt 15c, which possesses antibacterial activity against both Gram-positive (MIC against Staphylococcus aureus = 8 μM) and Gram-negative bacteria (MIC against Escherichia coli = 16 μM, Pseudomonas aeruginosa = 63 μM) and disrupted 35% of pre-established S. aureus biofilms at 32 μM. Cytoplasmic membrane permeability and tethered bilayer lipid membranes (tBLMs) studies suggested that 15c acts as a bacterial membrane disruptor. In addition, in vitro toxicity studies showed that the potent compounds are non-toxic against human cells at therapeutic dosages.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.8.2471-2480.2003 ◽

2003 ◽

Vol 47 (8) ◽

pp. 2471-2480 ◽

Cited By ~ 20

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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In Vitro and In Vivo Antibacterial Activities of DW-224a, a New Fluoronaphthyridone

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01407-05 ◽

2006 ◽

Vol 50 (6) ◽

pp. 2261-2264 ◽

Cited By ~ 36

Author(s):

Hee-Soo Park ◽

Hyun-Joo Kim ◽

Min-Jung Seol ◽

Dong-Rack Choi ◽

Eung-Chil Choi ◽

...

Keyword(s):

Antibacterial Activities ◽

The Other ◽

Vitro Activity ◽

Gram Negative Bacteria ◽

In Vitro Activity ◽

Gram Positive ◽

Gram Negative ◽

Gram Positive Bacteria

ABSTRACT DW-224a showed the most potent in vitro activity among the quinolone compounds tested against clinical isolates of gram-positive bacteria. Against gram-negative bacteria, DW-224a was slightly less active than the other fluoroquinolones. The in vivo activities of DW-224a against gram-positive bacteria were more potent than those of other quinolones.

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In Vitro and In Vivo Activities of DA-7867, a New Oxazolidinone, against Aerobic Gram-Positive Bacteria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.6.2498-2500.2005 ◽

2005 ◽

Vol 49 (6) ◽

pp. 2498-2500 ◽

Cited By ~ 7

Author(s):

Eun Jeong Yoon ◽

Yeong Woo Jo ◽

Sung Hak Choi ◽

Tae Ho Lee ◽

Jae Keol Rhee ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Streptococcus Pneumoniae ◽

Gram Positive ◽

Methicillin Resistant ◽

Gram Positive Bacteria ◽

Vancomycin Resistant Enterococci ◽

Infection Models ◽

Vancomycin Resistant

ABSTRACT In vitro and in vivo activities of DA-7867 were assessed against methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. All isolates were inhibited by DA-7867 at ≤0.78 μg/ml, a four-times-lower concentration than that of inhibition by linezolid. For murine infection models, DA-7867 also exhibited greater efficacy than linezolid against all isolates tested.

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