scholarly journals Mycobacterium tuberculosis β-Carbonic Anhydrases: Novel Targets for Developing Antituberculosis Drugs

2019 ◽  
Vol 20 (20) ◽  
pp. 5153 ◽  
Author(s):  
Aspatwar ◽  
Kairys ◽  
Rala ◽  
Parikka ◽  
Bozdag ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pathogenic Bacteria ◽  
Bacterial Species ◽  
In Vivo Studies ◽  
Close Relative ◽  
Carbonic Anhydrases ◽  
In Vitro Inhibition ◽  
Inhibition Studies

The genome of Mycobacterium tuberculosis (Mtb) encodes three β-carbonic anhydrases (CAs, EC 4.2.1.1) that are crucial for the life cycle of the bacterium. The Mtb β-CAs have been cloned and characterized, and the catalytic activities of the enzymes have been studied. The crystal structures of two of the enzymes have been resolved. In vitro inhibition studies have been conducted using different classes of carbonic anhydrase inhibitors (CAIs). In vivo inhibition studies of pathogenic bacteria containing β-CAs showed that β-CA inhibitors effectively inhibited the growth of pathogenic bacteria. The in vitro and in vivo studies clearly demonstrated that β-CAs of not only mycobacterial species, but also other pathogenic bacteria, can be targeted for developing novel antimycobacterial agents for treating tuberculosis and other microbial infections that are resistant to existing drugs. In this review, we present the molecular and structural data on three β-CAs of Mtb that will give us better insights into the roles of these enzymes in pathogenic bacterial species. We also present data from both in vitro inhibition studies using different classes of chemical compounds and in vivo inhibition studies focusing on M. marinum, a model organism and close relative of Mtb.

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 Carbonic Anhydrase Inhibitors as Novel Drugs against Mycobacterial β-Carbonic Anhydrases: An Update on In Vitro and In Vivo Studies

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2911 ◽  
Author(s):  
Ashok Aspatwar ◽  
Jean-Yves Winum ◽  
Fabrizio Carta ◽  
Claudiu Supuran ◽  
Milka Hammaren ◽  
...  
Keyword(s):  
Drug Targets ◽  
Treatment Strategies ◽  
In Vivo Studies ◽  
Carbonic Anhydrases ◽  
Novel Approach ◽  
Novel Drugs ◽  
Novel Treatment Strategies ◽  
Inhibition Studies

Mycobacteria cause a variety of diseases, such as tuberculosis, leprosy, and opportunistic diseases in immunocompromised people. The treatment of these diseases is problematic, necessitating the development of novel treatment strategies. Recently, β-carbonic anhydrases (β-CAs) have emerged as potential drug targets in mycobacteria. The genomes of mycobacteria encode for three β-CAs that have been cloned and characterized from Mycobacterium tuberculosis (Mtb) and the crystal structures of two of the enzymes have been determined. Different classes of inhibitor molecules against Mtb β-CAs have subsequently been designed and have been shown to inhibit these mycobacterial enzymes in vitro. The inhibition of these centrally important mycobacterial enzymes leads to reduced growth of mycobacteria, lower virulence, and impaired biofilm formation. Thus, the inhibition of β-CAs could be a novel approach for developing drugs against the severe diseases caused by pathogenic mycobacteria. In the present article, we review the data related to in vitro and in vivo inhibition studies in the field.

scholarly journals Study of Antimicrobial, Antioxidant and Cytotoxicity Properties of Selected Plant Extracts for Food Preservative Applications

2021 ◽  
pp. 95-111
Author(s):  
Tania Islam ◽  
Md Nazrul Islam ◽  
Wahidu Zzaman ◽  
Md Morsaline Billah
Keyword(s):  
Pathogenic Bacteria ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Antimicrobial Properties ◽  
In Vivo Studies ◽  
Diffusion Method ◽  
Plant Materials ◽  
Food Preservative

An attempt has been made to evaluate antimicrobial, antioxidant and cytotoxicity properties of extracts from onion (Allium cepa L.), garlic (Allium sativum), leaves of guava (Psidium guajava), papaya (Carica papaya), tea (Camellia sinensis), baen (Avicennia alba) and keora (Sonneratia apetala), respectively to apply as natural preservatives for tomatoes. The air-dried plant materials of the respective plant species were subjected to ethanol-methanol extraction, concentrated and stored at 4 °C before use. The extracts were dissolved in 95% ethanol for analysis of antioxidant and antimicrobial properties. Of the extracts tested, tea extracts showed the highest zone of inhibition against several pathogenic bacteria (E. coli 35.0±3.2 mm; P. aeruginosa 29.3±2.6 mm; S. typhi 28.4±2.1 mm and S. pyogenes 27.7±3.7 mm) using the disc diffusion method. In regard to DPPH free radical scavenging assay, keora and guava extracts showed the highest percentage of radical scavenging activity with the values of 89.64± 0.18 and 89.39± 0.88, respectively, which were in agreement with higher total antioxidant capacity (TAC) of these extracts obtained by the phosphomolybdenum method. Brine shrimp lethality bioassay for cytotoxicity assessment showed LC50 of 132.54 ± 18.99 µg/mL for the leaf extract of keora which was found to be most toxic among all studied extracts. The initial results indicated that the extracts could be used for food preservative applications based on the antimicrobial, antioxidant and cytotoxicity properties of the tested extracts. However, efficacy, stability and safety issues need to be addressed with both in vitro and in vivo studies.

scholarly journals Chloramphenicol Resurrected: A Journey from Antibiotic Resistance in Eye Infections to Biofilm and Ocular Microbiota

2019 ◽  
Vol 7 (9) ◽  
pp. 278 ◽  
Author(s):  
Lorenzo
Keyword(s):  
Pathogenic Bacteria ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
In Vivo Studies ◽  
Antibiofilm Activity ◽  
Eye Infections ◽  
Treatment And Prevention ◽  
Old Drugs

The advent of multidrug resistance among pathogenic bacteria is devastating the worth of antibiotics and changing the way of their administration, as well as the approach to use new or old drugs. The crisis of antimicrobial resistance is also due to the unavailability of newer drugs, attributable to exigent regulatory requirements and reduced financial inducements. The emerging resistance to antibiotics worldwide has led to renewed interest in old drugs that have fallen into disuse because of toxic side effects. Thus, comprehensive efforts are needed to minimize the pace of resistance by studying emergent microorganisms and optimize the use of old antimicrobial agents able to maintain their profile of susceptibility. Chloramphenicol is experiencing its renaissance because it is widely used in the treatment and prevention of superficial eye infections due to its broad spectrum of activity and other useful antimicrobial peculiarities, such as the antibiofilm properties. Concerns have been raised in the past for the risk of aplastic anemia when chloramphenicol is given intravenously. Chloramphenicol seems suitable to be used as topical eye formulation for the limited rate of resistance compared to fluoroquinolones, for its scarce induction of bacterial resistance and antibiofilm activity, and for the hypothetical low impact on ocular microbiota disturbance. Further in-vitro and in vivo studies on pharmacodynamics properties of ocular formulation of chloramphenicol, as well as its real impact against biofilm and the ocular microbiota, need to be better addressed in the near future.

Favorable effects in vitro and in vivo of two clinical isolates of Pseudomonas aeruginosa on nutritionally deficient Staphylococcus aureus strains

1973 ◽  
Vol 19 (8) ◽  
pp. 973-981 ◽  
Author(s):  
T. Gadbois ◽  
J. De Repentigny ◽  
L. G. Mathieu
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Peritoneal Cavity ◽  
Pathogenic Bacteria ◽  
Bacterial Species ◽  
Mixed Cultures ◽  
Rabbit Skin ◽  
Metabolic Activities

We have studied aspects of interbacterial ecology with nutritionally dependent Staphylococcus aureus strains; they were grown in association with Pseudomonas aeruginosa in systems of mixed cultures and infections in vitro in a semisynthetic medium and in vivo in mouse peritoneal cavity and rabbit skin. In mixed cultures and in P. aeruginosa culture filtrates, thymine and tryptophan deficiencies in staphylococci were partly overcome. This is probably because P. aeruginosa supplied the essential metabolites required to ensure growth; however, other metabolic activities could also be involved. Other experiments showed that the sensitivity of thymineless staphylococci to nucleoside inhibitions was alleviated. In mixed infections with P. aeruginosa, the S. aureus thymineless strain has shown a greater ability to survive in the peritoneal cavity of mice than when injected alone, even when one species was injected after the other with different doses of bacteria. The examination of the liquid from the peritoneal cavity of infected mice by fluorescence microscopy after fluorochroming with acridine orange or auramine O has revealed that Pseudomonas endotoxin seems to damage leucocytes and consequently reduces the phagocytosis of Staphylococcus cells.Necrosis in rabbit skin was mainly due to S. aureus when both species were injected together intradermally; the thymineless strain was less harmful than the parent strain.It seems that survival and even growth of nutritionally dependent strains of a bacterial species can be favored by the metabolic activities of another species in mixed cultures and infections, in this instance S. aureus by P. aeruginosa. This phenomenon among others could be a determinant of bacterial pathogenicity for nutritionally dependent pathogenic bacteria; thus associated organisms could determine the effective pathogenicity of nutritionally dependent bacteria by contributing essential nutrilites at the site where infection is initiated.

scholarly journals Developing an antibiotic effective against multi-drug resistant bacteria.

2014 ◽  
Vol 70 (a1) ◽  
pp. C714-C714
Author(s):  
Calvin Steussy ◽  
Cynthia Stauffacher ◽  
Mark Lipton ◽  
Mohamed Seleem
Keyword(s):  
Pathogenic Bacteria ◽  
Modern Medicine ◽  
In Vivo Studies ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Lead Compound ◽  
Drug Resistant Bacteria ◽  
Coa Reductase

The emergence of multi-drug resistant pathogenic bacteria is one of the great challenges to modern medicine. The gram positive cocci Methicillin Resistant Staphylococcus aureus (MRSA) and Vancomycin Resistant Enterococcus faecalis (VRE) are two particularly virulent examples. In vivo studies have shown that the eukaryotic like 'mevalonate' isoprenoid pathway used by these pathogenic cocci is essential to their growth and virulence [1]. Our structures of HMG-CoA reductase (HMGR) from P. mevalonii demonstrated that the bacterial enzymes are structurally distinct from the human enzymes allowing for specific antibacterial activity [2]. High throughput in vitro screening against bacterial HMGR at the Southern Research Center, Birmingham, AL uncovered a lead compound with an IC50 of 80 µM with a competitive mode of action. Our x-ray crystal structures of HMGR from E. faecalis complexed with the lead compound and its variations have informed the synthesis of new inhibitors that have improved the IC50 to 5 µM [3]. Studies of this compound show it to be active against both MRSA and VRE in culture, effective against these bacteria in biofilms, and efficacious in a model system of eukaryotic infection. Structures and kinetics of these compounds will be presented and future directions discussed.

scholarly journals Preliminary Study on the Effect of Quinolone against Rec A Protein for the Possible Role in the Treatment of Tuberculosis through Molecular Docking

2021 ◽  
Vol 9 (VII) ◽  
pp. 227-232
Author(s):  
Priyanka Gautam
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Chronic Disease ◽  
In Vivo Studies ◽  
Online Database ◽  
Docking Method ◽  
Preliminary Study ◽  
Molecular Docking Method

Tuberculosis is a type of ancient, chronic disease which affects humans and caused by Mycobacterium tuberculosis. They affect the lungs and other organs. The treatment is curable but in some cases it is fatal if not treated properly. The molecular docking method was used to see the interaction of the protein with the ligand. Thus, molecular docking was used to analyse the Rec A (PDB ID 1U94) target protein with their known type of ligand by using molecular docking tools. The Rec A (PDB ID 1U94) structure of protein was downloaded through online database. The best ligand after molecular docking was Quinolone, which may act as a drug after in vitro and in vivo studies.

scholarly journals Screening of Probiotic Activities of Forty-Seven Strains of Lactobacillus spp. by In Vitro Techniques and Evaluation of the Colonization Ability of Five Selected Strains in Humans

1999 ◽  
Vol 65 (11) ◽  
pp. 4949-4956 ◽  
Author(s):  
C. N. Jacobsen ◽  
V. Rosenfeldt Nielsen ◽  
A. E. Hayford ◽  
P. L. Møller ◽  
K. F. Michaelsen ◽  
...  
Keyword(s):  
Washout Period ◽  
Pathogenic Bacteria ◽  
Model Systems ◽  
In Vivo Studies ◽  
Enzyme Analysis ◽  
Restriction Enzyme Analysis ◽  
Fecal Samples ◽  
Freeze Dried

ABSTRACT The probiotic potential of 47 selected strains ofLactobacillus spp. was investigated. The strains were examined for resistance to pH 2.5 and 0.3% oxgall, adhesion to Caco-2 cells, and antimicrobial activities against enteric pathogenic bacteria in model systems. From the results obtained in vitro, five strains,Lactobacillus rhamnosus 19070-2, L. reuteri DSM 12246, L. rhamnosus LGG, L. delbrueckii subsp.lactis CHCC 2329, and L. casei subsp.alactus CHCC 3137, were selected for in vivo studies. The daily consumption by 12 healthy volunteers of two doses of 1010 freeze-dried bacteria of the selected strains for 18 days was followed by a washout period of 17 days. Fecal samples were taken at days 0 and 18 and during the washout period at days 5 and 11.Lactobacillus isolates were initially identified by API 50CHL and internal transcribed spacer PCR, and their identities were confirmed by restriction enzyme analysis in combination with pulsed-field gel electrophoresis. Among the tested strains, L. rhamnosus 19070-2, L. reuteri DSM 12246, and L. rhamnosus LGG were identified most frequently in fecal samples; they were found in 10, 8, and 7 of the 12 samples tested during the intervention period, respectively, whereas reisolations were less frequent in the washout period. The bacteria were reisolated in concentrations from 105 to 108 cells/g of feces. Survival and reisolation of the bacteria in vivo appeared to be linked to pH tolerance, adhesion, and antimicrobial properties in vitro.

scholarly journals The Role of Iron and Siderophores in Infection, and the Development of Siderophore Antibiotics

2019 ◽  
Vol 69 (Supplement_7) ◽  
pp. S529-S537 ◽  
Author(s):  
Malcom G P Page
Keyword(s):  
Outer Membrane ◽  
Pathogenic Bacteria ◽  
Phase 1 ◽  
Bacterial Species ◽  
Multidrug Resistant ◽  
Membrane Receptors ◽  
Transport Systems ◽  
Resistant Bacteria

Abstract Iron is an essential nutrient for bacterial growth, replication, and metabolism. Humans store iron bound to various proteins such as hemoglobin, haptoglobin, transferrin, ferritin, and lactoferrin, limiting the availability of free iron for pathogenic bacteria. However, bacteria have developed various mechanisms to sequester or scavenge iron from the host environment. Iron can be taken up by means of active transport systems that consist of bacterial small molecule siderophores, outer membrane siderophore receptors, the TonB-ExbBD energy-transducing proteins coupling the outer and the inner membranes, and inner membrane transporters. Some bacteria also express outer membrane receptors for iron-binding proteins of the host and extract iron directly from these for uptake. Ultimately, iron is acquired and transported into the bacterial cytoplasm. The siderophores are small molecules produced and released by nearly all bacterial species and are classified according to the chemical nature of their iron-chelating group (ie, catechol, hydroxamate, α-hydroxyl-carboxylate, or mixed types). Siderophore-conjugated antibiotics that exploit such iron-transport systems are under development for the treatment of infections caused by gram-negative bacteria. Despite demonstrating high in vitro potency against pathogenic multidrug-resistant bacteria, further development of several candidates had stopped due to apparent adaptive resistance during exposure, lack of consistent in vivo efficacy, or emergence of side effects in the host. However, cefiderocol, with an optimized structure, has advanced and has been investigated in phase 1 to 3 clinical trials. This article discusses the mechanisms implicated in iron uptake and the challenges associated with the design and utilization of siderophore-mimicking antibiotics.

THE ANTIBACTERIAL SPECTRUM OF USTILAGIC ACID

1953 ◽  
Vol 31 (6) ◽  
pp. 505-511
Author(s):  
R. W. Reed ◽  
M. A. Holder
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Oral Administration ◽  
Pathogenic Bacteria ◽  
Antibacterial Effect ◽  
Gram Negative ◽  
In Vitro Inhibition ◽  
Urine Levels ◽  
Antibacterial Spectrum ◽  
Serum And Urine

Ustilagic acid is shown to be relatively inactive against common Gram-positive and Gram-negative pathogenic bacteria and against Mycobacterium tuberculosis. Serum and urine levels in rabbits following oral administration are much lower than the concentration required for in vitro inhibition of most bacteria tested. Human serum depresses the antibacterial effect of ustilagic acid in vitro. The drug had no effect on the course of experimental infection in mice.

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