Novel isoniazid derivative as promising antituberculosis agent

Background: A major focus of tuberculosis drug discovery is aimed at the development of novel antibiotics with activity against drug-resistant strains of Mycobacterium tuberculosis. Results: We have synthesized ten isoniazid derivatives and investigated for antibacterial activity toward M. tuberculosis H37Rv and isoniazid-resistant strain SRI 1369. It was revealed that only one compound, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide (1), is active toward isoniazid-resistant strain with minimum inhibitory concentration value of 0.14 μM. This compound is not cytotoxic toward human liver cells (HepG2; IC50 >100 μM), demonstrates good permeability in Caco-2 cells. Accordingly to the results of plasma protein binding assay, unbound fraction of compound 1, which potentially exhibits pharmacologic effects, is 57.9%. Conclusion: Therefore, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide is a promising compound for further preclinical studies.

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Use of the NP-40 Detergent-Mediated Assay in Discovery of Inhibitors of β-Hematin Crystallization

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00121-11 ◽

2011 ◽

Vol 55 (7) ◽

pp. 3363-3369 ◽

Cited By ~ 66

Author(s):

Rebecca D. Sandlin ◽

Melissa D. Carter ◽

Patricia J. Lee ◽

Jennifer M. Auschwitz ◽

Susan E. Leed ◽

...

Keyword(s):

Drug Target ◽

Inhibitory Concentration ◽

Protozoan Parasite ◽

Drug Resistant ◽

Digestive Vacuole ◽

Content Type ◽

Parasite Survival ◽

Resistant Strains ◽

Drug Resistant Strains ◽

Important Drug

ABSTRACTThe protozoan parasite responsible for malaria affects over 500 million people each year. Current antimalarials have experienced decreased efficacy due to the development of drug-resistant strains ofPlasmodiumspp., resulting in a critical need for the discovery of new antimalarials. Hemozoin, a crystalline by-product of heme detoxification that is necessary for parasite survival, serves as an important drug target. The quinoline antimalarials, including amodiaquine and chloroquine, act by inhibiting the formation of hemozoin. The formation of this crystal does not occur spontaneously, and recent evidence suggests crystallization occurs in the presence of neutral lipid particles located in the acidic digestive vacuole of the parasite. To mimic these conditions, the lipophilic detergent NP-40 has previously been shown to successfully mediate the formation of β-hematin, synthetic hemozoin. Here, an NP-40 detergent-based assay was successfully adapted for use as a high-throughput screen to identify inhibitors of β-hematin formation. The resulting assay exhibited a favorableZ′ of 0.82 and maximal drift of less than 4%. The assay was used in a pilot screen of 38,400 diverse compounds at a screening concentration of 19.3 μM, resulting in the identification of 161 previously unreported β-hematin inhibitors. Of these, 48 also exhibited ≥90% inhibition of parasitemia in aPlasmodium falciparumwhole-cell assay at a screening concentration of 23 μM. Eight of these compounds were identified to have nanomolar 50% inhibitory concentration values near that of chloroquine in this assay.

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Semi-Synthesis of Marine-Derived Ilamycin F Derivatives and Their Antitubercular Activities

Frontiers in Chemistry ◽

10.3389/fchem.2021.774555 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jun Li ◽

Zhiyong Liu ◽

Mingye Hong ◽

Changli Sun ◽

Tianyu Zhang ◽

...

Keyword(s):

Prevention And Control ◽

Inhibitory Concentration ◽

Drug Resistant ◽

Structure Activity ◽

The World ◽

Resistant Strains ◽

New Challenges ◽

Low Cytotoxicity ◽

Drug Resistant Strains ◽

And Control

Tuberculosis (TB) is still a global disease threatening people’s lives. With the emergence of multi-drug-resistant Mycobacterium tuberculosis the prevention and control of tuberculosis faces new challenges, and the burden of tuberculosis treatment is increasing among the world. Ilamycins are novel cyclopeptides with potent anti-TB activities, which have a unique target protein against M. tuberculosis and drug-resistant strains. Herein, ilamycin F, a major secondary metabolite isolated from the marine-derived mutant strain Streptomyces atratus SCSIO ZH16 ΔilaR, is used as a scaffold to semi-synthesize eighteen new ilamycin derivatives (ilamycin NJL1–NJL18, 1–18). Our study reveals that four of ilamycin NJLs (1, 6, 8, and 10) have slightly stronger anti-TB activities against Mtb H37Rv (minimum inhibitory concentration, 1.6–1.7 μM) compared with that of ilamycin F on day 14th, but obviously display more potent activities than ilamycin F on day 3rd, indicating anti-TB activities of these derivatives with fast-onset effect. In addition, cytotoxic assays show most ilamycin NJLs with low cytotoxicity except ilamycin NJL1 (1). These findings will promote the further exploration of structure-activity relationships for ilamycins and the development of anti-TB drugs.

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Antimicrobial Activity of Extracts of Two Native Fruits of Chile: Arrayan (Luma apiculata) and Peumo (Cryptocarya alba)

Antibiotics ◽

10.3390/antibiotics9080444 ◽

2020 ◽

Vol 9 (8) ◽

pp. 444

Author(s):

Jitka Viktorová ◽

Rohitesh Kumar ◽

Kateřina Řehořová ◽

Lan Hoang ◽

Tomas Ruml ◽

...

Keyword(s):

Mass Spectrometry ◽

Inhibitory Concentration ◽

Dependent Manner ◽

Drug Resistant ◽

Planktonic Cells ◽

Fruit Extract ◽

Concentration Dependent Manner ◽

Autoinducer 2 ◽

Resistant Strains ◽

Drug Resistant Strains

Arrayan and peumo fruits are commonly used in the traditional medicine of Chile. In this study, the concentration of the extracts halving the bacterial viability and biofilms formation and disruption of the drug-sensitive and drug-resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa was determined. The chemical composition of extracts was analyzed by high-resolution liquid chromatography coupled with mass spectrometry (U-HPLC/MS). The arrayan extract (Inhibitory concentration IC50 0.35 ± 0.01 mg/mL) was more effective than peumo extract (IC50 0.53 ± 0.02 mg/mL) in the inhibition of S. aureus planktonic cells. Similarly, the arrayan extract was more effective in inhibiting the adhesion (S. aureus IC50 0.23 ± 0.02 mg/mL, P. aeruginosa IC50 0.29 ± 0.02 mg/mL) than peumo extracts (S. aureus IC50 0.47 ± 0.03 mg/mL, P. aeruginosa IC50 0.35 ± 0.01 mg/mL). Both extracts inhibited quorum sensing in a concentration-dependent manner, and the most significant was the autoinducer-2 type communication inhibition by arrayan extract. Both extracts also disrupted preformed biofilm of P. aeruginosa (arrayan IC50 0.56 ± 0.04 mg/mL, peumo IC50 0.59 ± 0.04 mg/mL). However, neither arrayan nor peumo extracts disrupted S. aureus mature biofilm. U-HPLC/MS showed that both fruit extracts mainly possessed quercetin compounds; the peumo fruit extract also contained phenolic acids and phenylpropanoids. Our results suggested that both extracts could be used as natural antimicrobials for some skin and nosocomial infections.

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The development of drug-resistant strains of Eimeria maxima in the laboratory

Parasitology ◽

10.1017/s0031182000053233 ◽

1975 ◽

Vol 71 (1) ◽

pp. 153-165 ◽

Cited By ~ 21

Author(s):

C. C. Norton ◽

L. P. Joyner

Keyword(s):

Drug Administration ◽

Resistant Strain ◽

Parent Strain ◽

Drug Resistant ◽

Development Of Resistance ◽

Eimeria Maxima ◽

Resistant Strains ◽

Drug Dependent ◽

Drug Resistant Strains

The development of strains of Eimeria maxima resistant to buquinolate, methyl benzoquate, clopidol, sulphaquinoxaline and robenidine is described. It was not possible to standardize a schedule of inoculations and drug administration, which would enable the development of resistance to the different drugs to be compared directly. Resistance developed most readily to the quinolones. One robenidine-resistant strain proved to be drug-dependent. Dinitolmide showed unusual effects upon sporogony and three attempts to develop resistance against this activity failed. Chicks previously immunized with the parent strain were completely protected against infection with the drug-resistant strains.

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Modified Fixed-Ratio Isobologram Method for Studying In Vitro Interactions between Atovaquone and Proguanil or Dihydroartemisinin against Drug-Resistant Strains of Plasmodium falciparum

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.11.4097-4102.2004 ◽

2004 ◽

Vol 48 (11) ◽

pp. 4097-4102 ◽

Cited By ~ 163

Author(s):

Quinton L. Fivelman ◽

Ipemida S. Adagu ◽

David C. Warhurst

Keyword(s):

Plasmodium Falciparum ◽

Treatment Failure ◽

Resistant Strain ◽

Fixed Ratio ◽

Drug Resistant ◽

Resistant Strains ◽

Drug Resistant Strains ◽

In Vitro Interactions

ABSTRACT A modified fixed-ratio isobologram method for studying the in vitro interactions between antiplasmodial drugs is described. This method was used to examine the interactions between atovaquone, proguanil, and dihydroartemisinin. The interaction between atovaquone and proguanil was synergistic against atovaquone-sensitive strains K1 and T996; however, there was a loss of synergy against atovaquone-resistant strain NGATV01 isolated after Malarone (the combination of atovaquone and proguanil) treatment failure. While the interaction between atovaquone and dihydroartemisinin was indifferent against isolate NGATV01, the interaction displayed indifference tending toward antagonism against the atovaquone-sensitive strains tested. The relevance of in vitro interactions to in vivo treatment is discussed.

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Immunity in trypanosomiasis

Parasitology ◽

10.1017/s0031182000026780 ◽

1959 ◽

Vol 49 (1-2) ◽

pp. 143-152 ◽

Cited By ~ 17

Author(s):

M. A. Soltys

Keyword(s):

Resistant Strain ◽

Therapeutic Dose ◽

Sensitive Strain ◽

Drug Resistant ◽

Chemotherapeutic Drugs ◽

Natural Conditions ◽

Resistant Strains ◽

Drug Resistant Strains

Antibody-resistant strains are less sensitive to suramin and antrycide than antibody-sensitive strains. When living trypanosomes were exposed to suramin and antrycide in vitro, antibody-resistant strains needed 50 times more drugs than antibody-sensitive trypanosomes in order to make them non-infectious to mice. In therapeutic experiments in mice the minimal therapeutic dose of drugs for antibody-sensitive strains was 0·1 mg. but for resistant strains it was 0·3 mg./20 g. mice. Rabbits treated prophylactically with suramin resisted infection with the antibody-sensitive strain for a period of 4 months, but failed to resist infection with the antibody-resistant strain after 2 months.Rabbits treated prophylactically with antrycide pro-salt, resisted infection with antibody-sensitive strains for a period of 2 months, but failed to resist infection with the antibody-resistant strain even 1 month after injection with the drug. Although trypanosomes can become drug resistant without being antibody resistant it is suggested that, under natural conditions, drug-resistant strains in animals and man develop from antibody-resistant strains, particularly when trypanostatic drugs are used. It is suggested in conclusion from these experiments that strains of trypanosomes which are exposed for some time to antibodies and become antibody resistant after passage through animals like rabbits, as well as those strains frequently passaged through mice, should be used in all tests for the efficiency of chemotherapeutic drugs.

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Omadacycline Potentiates Clarithromycin Activity Against Mycobacterium abscessus

Frontiers in Pharmacology ◽

10.3389/fphar.2021.790767 ◽

2021 ◽

Vol 12 ◽

Author(s):

Bui Thi Bich Hanh ◽

Nguyen Thanh Quang ◽

Yujin Park ◽

Bo Eun Heo ◽

Seunghyeon Jeon ◽

...

Keyword(s):

Concentration Index ◽

Inhibitory Concentration ◽

Mycobacterium Abscessus ◽

Respiratory Pathogen ◽

Drug Resistant ◽

Zebrafish Model ◽

Resistant Strains ◽

Drug Resistant Strains ◽

Positive Effect

Mycobacterium abscessus is a difficult respiratory pathogen to treat, when compared to other nontuberculus mycobacteria (NTM), due to its drug resistance. In this study, we aimed to find a new clarithromycin partner that potentiated strong, positive, synergy against M. abscessus among current anti-M. abscessus drugs, including omadacycline, amikacin, rifabutin, bedaquiline, and cefoxitine. First, we determined the minimum inhibitory concentrations required of all the drugs tested for M. abscessus subsp. abscessus CIP104536T treatment using a resazurin microplate assay. Next, the best synergistic partner for clarithromycin against M. abscessus was determined using an in vitro checkerboard combination assay. Among the drug combinations evaluated, omadacycline showed the best synergistic effect with clarithromycin, with a fractional inhibitory concentration index of 0.4. This positive effect was also observed against M. abscessus clinical isolates and anti-M. abscessus drug resistant strains. Lastly, this combination was further validated using a M. abscessus infected zebrafish model. In this model, the clarithromycin-omadacyline regimen was found to inhibit the dissemination of M. abscessus, and it significantly extended the lifespan of the M. abscessus infected zebrafish. In summation, the synergy between two anti-M. abscessus compounds, clarithromycin and omadacycline, provides an attractive foundation for a new M. abscessus treatment regimen.

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