C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus

Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin. Unlike rifampicin, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, rifampicin or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.

Download Full-text

Blocking bacterial naphthohydroquinone oxidation and ADP-ribosylation improves activity of rifamycins against Mycobacterium abscessus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00978-21 ◽

2021 ◽

Author(s):

Uday S. Ganapathy ◽

Tian Lan ◽

Philipp Krastel ◽

Marissa Lindman ◽

Matthew D. Zimmerman ◽

...

Keyword(s):

Comparative Analysis ◽

Mycobacterium Abscessus ◽

Bacterial Metabolism ◽

Proof Of Concept ◽

Intrinsic Resistance ◽

Bacterial Oxidation ◽

Adp Ribosylation ◽

Dual Mechanism ◽

Adp Ribosyltransferase

Rifampicin is an effective drug for treating tuberculosis (TB) but is not used to treat M. abscessus infections due to poor in vitro activity. While rifabutin, another rifamycin, has better anti- M. abscessus activity, its activity is far from the nanomolar potencies of rifamycins against M. tuberculosis . Here, we asked i) why is rifabutin more active against M. abscessus than rifampicin, and ii) why is rifabutin’s anti- M. abscessus activity poorer than its anti-TB activity. Comparative analysis of naphthoquinone versus naphthohydroquinone-containing rifamycins suggested that the improved activity of rifabutin over rifampicin is linked to its less readily oxidizable naphthoquinone core. Although rifabutin is resistant to bacterial oxidation, metabolite and genetic analyses showed that this rifamycin is metabolized by the ADP-ribosyltransferase Arr Mab like rifampicin, preventing it from achieving the nanomolar activity it displays against M. tuberculosis . Based on the identified dual mechanism of intrinsic rifamycin resistance, we hypothesized that rifamycins more potent than rifabutin should contain the molecule’s naphthoquinone core plus a modification that blocks ADP-ribosylation at its C23. To test these predictions, we performed a blinded screen of a diverse collection of 189 rifamycins and identified two molecules more potent than rifabutin. As predicted, these compounds contained both a more oxidatively-resistant naphthoquinone core and C25 modifications that blocked ADP-ribosylation. Together, this work revealed dual bacterial metabolism as the mechanism of intrinsic resistance of M. abscessus to rifamycins and provides proof of concept for the repositioning of rifamycins for M. abscessus disease by developing derivatives that resist both bacterial oxidation and ADP-ribosylation.

Download Full-text

Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates TargetingMycobacterium tuberculosisandMycobacterium abscessus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01696-17 ◽

2018 ◽

Vol 62 (5) ◽

Cited By ~ 6

Author(s):

Rashmi Gupta ◽

Carolina Rodrigues Felix ◽

Matthew P. Akerman ◽

Kate J. Akerman ◽

Cathryn A. Slabber ◽

...

Keyword(s):

Mycobacterium Abscessus ◽

Cross Resistance ◽

Human Pathogens ◽

Intrinsic Resistance ◽

Content Type ◽

Starting Point ◽

Scalable Synthesis ◽

High Level ◽

Novel Drug

ABSTRACTMycobacterium tuberculosisand the fast-growing speciesMycobacterium abscessusare two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistantM. tuberculosisstrains and the high level of intrinsic resistance ofM. abscessuscall for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), againstM. abscessusandM. tuberculosis. We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicatingin vitroconditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverseM. tuberculosisandM. abscessusclinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target theM. tuberculosisgyrase.In vitroenzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity againstM. tuberculosisandM. abscessusthat act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.

Download Full-text

AN IN VITRO INVESTIGATION OF ANTIMICROBIAL EFFICACY OF EUPHORBIA HIRTA AND MURRAYA KOENIGII AGAINST SELECTED PATHOGENIC MICROORGANISMS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i5.24578 ◽

2018 ◽

Vol 11 (5) ◽

pp. 359 ◽

Cited By ~ 4

Author(s):

Divya Gupta ◽

Mukesh Kumar ◽

Vishal Gupta

Keyword(s):

Antimicrobial Activity ◽

Inhibitory Activity ◽

Diffusion Method ◽

Synergistic Activity ◽

Pathogenic Microorganisms ◽

Disc Diffusion ◽

Murraya Koenigii ◽

Euphorbia Hirta ◽

In Vitro Investigation ◽

Antibiotics Susceptibility

Objective: To investigate the solvent-dependent antimicrobial activity and phytochemical analysis of extracts of Euphorbia hirta (leaves and flowers) and Murraya koenigii (leaves), as well as to evaluate the synergistic activity of these medicinal extracts with suitable antibiotic discs and antibiotics susceptibility of selected pathogenic microorganisms.Methods: The antimicrobial activity of the medicinal extracts was screened through agar well diffusion method and antibiotics susceptibility of selected microorganisms was investigated using disc diffusion method. A combined agar well diffusion and disc diffusion methods were used for the determination of synergistic activities of the extracts with antibiotic discs.Results: Among the different solvents, ethanol had maximum zone of inhibition against the test pathogens. Ethanolic leaf extracts of E. hirta exhibited the highest inhibitory activity against Candida albicans and Staphylococcus aureus with minimum inhibitory concentration value of 12.5 mg/mL and 25.0 mg/mL, respectively. Antimicrobial assay revealed that E. hirta extracts were active against all tested Gram-negative bacteria. However, none of the plant extracts had inhibitory activity against Gram-positive bacterium Propionibacterium acnes. Phytochemical screening for both the extracts from E. hirta revealed the presence of steroid, tannin, terpenoids, carbohydrates, alkaloid, flavonoid, diterpene, and glycoside, whereas M. koenigii extract was rich in saponins, protein, steroid, tannin, carbohydrates, alkaloid, flavonoid, and glycoside.Conclusion: The present study proposes that E. hirta and M. koenigii extracts are excellent sources of natural bioactive compounds that could be used as potent antimicrobial drugs to counter the emerging problem of antibiotic resistance of pathogenic microorganisms.

Download Full-text

Genome-Wide Essentiality Analysis of Mycobacterium abscessus by Saturated Transposon Mutagenesis and Deep Sequencing

mBio ◽

10.1128/mbio.01049-21 ◽

2021 ◽

Author(s):

Dalin Rifat ◽

Liang Chen ◽

Barry N. Kreiswirth ◽

Eric L. Nuermberger

Keyword(s):

Deep Sequencing ◽

Mycobacterium Abscessus ◽

Transposon Mutagenesis ◽

Comprehensive Analysis ◽

Data Sets ◽

Similar Data ◽

Intrinsic Resistance ◽

Effective Strategies ◽

Genome Wide

Limited knowledge regarding Mycobacterium abscessus pathogenesis and intrinsic resistance to most classes of antibiotics is a major obstacle to developing more effective strategies to prevent and mitigate disease. Using optimized procedures for Himar1 transposon mutagenesis and deep sequencing, we performed a comprehensive analysis to identify M. abscessus genetic elements essential for in vitro growth and compare them to similar data sets for M. tuberculosis and M. avium subsp. hominissuis .

Download Full-text

Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages.

Infection and Immunity ◽

10.1128/iai.57.3.845-849.1989 ◽

1989 ◽

Vol 57 (3) ◽

pp. 845-849 ◽

Cited By ~ 118

Author(s):

H W Murray ◽

A Szuro-Sudol ◽

D Wellner ◽

M J Oca ◽

A M Granger ◽

...

Keyword(s):

Antimicrobial Activity ◽

Respiratory Burst ◽

Gamma Interferon ◽

Human Macrophages ◽

Tryptophan Degradation

Download Full-text

Development of multifunctional polyacrylonitrile/silver nanocomposite films: Antimicrobial activity, catalytic activity, electrical conductivity, UV protection and SERS-active sensor

Journal of Materials Research and Technology ◽

10.1016/j.jmrt.2020.05.079 ◽

2020 ◽

Vol 9 (4) ◽

pp. 9380-9394 ◽

Cited By ~ 1

Author(s):

Mohamed Rehan ◽

Amr A. Nada ◽

Tawfik A. Khattab ◽

Nayera A.M. Abdelwahed ◽

Amira Adel Abou El-Kheir

Keyword(s):

Electrical Conductivity ◽

Antimicrobial Activity ◽

Catalytic Activity ◽

Uv Protection ◽

Nanocomposite Films ◽

Active Sensor ◽

Silver Nanocomposite

Download Full-text

Effects of Mono- and Disaccharides on the Antimicrobial Activity of Bovine Lactoperoxidase System

Journal of Food Protection ◽

10.4315/0362-028x.jfp-10-184 ◽

2011 ◽

Vol 74 (1) ◽

pp. 134-139 ◽

Cited By ~ 16

Author(s):

AHMAD NIMATULLAH AL-BAARRI ◽

MAKOTO HAYASHI ◽

MASAHIRO OGAWA ◽

SHIGERU HAYAKAWA

Keyword(s):

Antimicrobial Activity ◽

Catalytic Activity ◽

Kinetic Study ◽

Salmonella Enteritidis ◽

Sugar Content ◽

The Other ◽

Inhibitory Potency ◽

Lactoperoxidase System ◽

Noncompetitive Inhibitor

The effects of mono- and disaccharides on the antimicrobial activity of the lactoperoxidase (LPO) system against Salmonella Enteritidis were investigated. The results clearly reveal that most of the sugars inhibit the antimicrobial activity of the LPO system. The inhibitory potency varies depending on the structure of sugar. l-Fructose and d-allose were strongly inhibitive to the action of the LPO system, while sucrose was the weakest inhibitor. The decreased antimicrobial activity is due to the reduction of LPO catalytic activity by sugar. An inhibitory kinetic study showed the noncompetitive inhibitor. d-Allose and L-fructose yielded strikingly low Ki values of 0.36 and 0.42 mM, respectively, while the Ki values of the other sugars ranged from 1.37 to 3.60 mM. Since LPO activity is inhibited by the saccharides, the sugar content in food should be considered when the LPO system is applied to the preservation of food.

Download Full-text

Antimicrobial Activity of Gentiana lutea L. Extracts

Zeitschrift für Naturforschung C ◽

10.1515/znc-2009-5-606 ◽

2009 ◽

Vol 64 (5-6) ◽

pp. 339-342 ◽

Cited By ~ 22

Author(s):

Katarina Šavikin ◽

Nebojša Menković ◽

Gordana Zdunić ◽

Tatjana Stević ◽

Dragoja Radanović ◽

...

Keyword(s):

Antimicrobial Activity ◽

Candida Albicans ◽

Secondary Metabolites ◽

Antimicrobial Effect ◽

Gram Negative Bacteria ◽

Synergistic Activity ◽

Gram Negative ◽

Gentiana Lutea ◽

Methanolic Extracts ◽

Pure Compounds

Methanolic extracts of flowers and leaves of Gentiana lutea L., together with the isolated compounds mangiferin, isogentisin and gentiopicrin, were used to investigate the antimicrobial activity of the plant. A variety of Gram-positive and Gram-negative bacteria as well as the yeast Candida albicans has been included in this study. Both extracts and isolated compounds showed antimicrobial activity with MIC values ranging from 0.12 - 0.31 mg/ml. Our study indicated that the synergistic activity of the pure compounds may be responsible for the good antimicrobial effect of the extracts. Quantification of the secondary metabolites was performed using HPLC

Download Full-text

Modulatory antimicrobial activity of piper arboreum extracts

Acta Botanica Croatica ◽

10.2478/botcro-2013-0026 ◽

2014 ◽

Vol 73 (1) ◽

pp. 303-311 ◽

Cited By ~ 4

Author(s):

Saulo R. Tintino ◽

Celestina E. S. Souza ◽

Gláucia M. M. Guedes ◽

Jaqueline I. V. Costa ◽

Francisco M. Duarte ◽

...

Keyword(s):

Antimicrobial Activity ◽

Natural Products ◽

Ethanol Extract ◽

Antifungal Drugs ◽

Synergistic Activity ◽

Sexually Transmitted ◽

Microdilution Method ◽

Antibiotic Drugs ◽

Pharmacological Targets ◽

Microbial Infections

AbstractThe side effects of certain antibiotics have been a recent dilemma in the medical arena. Due this fact, the necessity of natural product discovery could provide important indications against several pharmacological targets and combat many infectious agents. Piper arboreum Aub. (Piperaceae) has been used by Brazilian traditional communities against several illnesses including rheumatism, bronchitis, sexually transmitted diseases and complaints of the urinary tract. Medicinal plants are a source of several remedies used in clinical practice to combat microbial infections. In this study, ethanol extract and fractions of Piper arboreum leaves were used to assay antimicrobial and modulatory activity. The minimum inhibitory concentration (MIC) was determined using microdilution method of ethanol extract and fractions from the leaves of P. arboreum ranging between 8 and 1024 μg mL-1. The capacity of these natural products to enhance the activity of antibiotic and antifungal drugs was also assayed. In these tests, natural products were combined with drugs. The natural products assayed did not demonstrate any clinically relevant antimicrobial activity (MIC ≥ 1024 μg mL-1). However, the modulation of antibiotic activity assay observed a synergistic activity of natural products combined with antifungal (such as nystatin and amphotericin B) and antibiotic drugs (such as amikacin, gentamicin and kanamycin). According to these results, these natural products can be an interesting alternative not only to combat infectious diseases caused by bacteria or fungi, but also to combat enhanced resistance of microorganisms to antibiotic and antifungal drugs.

Download Full-text