Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity against Rifampicin-resistant Mycobacterium tuberculosis

Nigam, Aeshna; Almabruk, Khaled H.; Saxena, Anupam; Yang, Jongtae; Mukherjee, Udita; Kaur, Hardeep; Kohli, Puneet; Kumari, Rashmi; Singh, Priya; Zakharov, Lev N.; Singh, Yogendra; Mahmud, Taifo; Lal, Rup

doi:10.1074/jbc.m114.572636

Cited by 45 publications

(80 citation statements)

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“…The numbers of species in this genus that are validly published have increased from 10 in 2000 to 68 in 2015 (http://www.bacterio.net/amycola topsis.html). These organisms possess several biosynthetic gene clusters (BGCs) that can be of biological importance [16], however the analysis based on the genome has been restricted to BGCs of balhimycin (bal), chloroeremomycin (cep) vancomycin (vcm), rifamycin (rif) [3,4]. The genomic studies have revealed that Amycolatopsis have comparatively large genomes *5 Mb (A. halophila YIM93223-10) to 10.86 Mb (A. balhimycina FH 1894), circular chromosomes and contains over 20 secondary metabolic gene clusters.…”

Section: General Features Of the Genus Amycolatopsismentioning

confidence: 99%

“…Within actinobacteria, members of genus Streptomyces contribute to almost 70-80 % of secondary metabolites while a small percentage is contributed by Amycolatopsis, Actinoplanes, Micromonospora and Saccharopolyspora [1]. Among these genera, the genus Amycolatopsis is of special importance for its capacity to produce several commercially and medicinally important antibiotics as balhimycin, vancomycin and rifamycin [2][3][4], other secondary metabolites as immuno-suppressants, anti-cancer agents etc. [5] and other applications [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

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Genetics and Genomics of the Genus Amycolatopsis

2016

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Actinobacteria are gram-positive filamentous bacteria which contains some of the most deadly human pathogens (Mycobacterium tuberculosis, M. leprae, Corynebacterium diphtheriae, Nocardia farcinica), plant pathogens (Streptomyces scabies, Leifsonia xyli) along with organisms that produces antibiotic (Streptomycetes, Amycolatopsis, Salinospora). Interestingly, these bacteria are equipped with an extraordinary capability of producing antibiotics and other metabolites which have medicinal properties. With the advent of inexpensive genome sequencing techniques and their clinical importance, many genomes of Actinobacteria have been successfully sequenced. These days, with the constant increasing number of drug-resistant bacteria, the urgent need for discovering new antibiotics has emerged as a major scientific challenge. And, unfortunately the traditional method of screening bacterial strains for the production of antibiotics has decreased leading to a paradigm shift in the planning and execution of discovery of novel biosynthetic gene clusters via genome mining process. The entire focus has shifted to the evaluation of genetic capacity of organisms for metabolite production and activation of cryptic gene clusters. This has been made possible only due to the availability of genome sequencing and has been augmented by genomic studies and new biotechnological approaches. Through this article, we present the analysis of the genomes of species belonging to the genus Amycolatopsis, sequenced till date with a focus on completely sequenced genomes and their application for further studies.

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Section: General Features Of the Genus Amycolatopsismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetics and Genomics of the Genus Amycolatopsis

2016

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“…Further testing of the analogue against MDR strains of M. tuberculosis was done in association with Institute of Genomics and Integrative Biology (CSIR-IGIB), Delhi. The analogue 24-desmethylrifampicin was found to be better than the already existing rifampicin used against MDR strains [19]. Thus it can be hypothesised that, this drug could find application in pharmaceutical sector.…”

Section: Modification Of Rifamycin Polyketide Backbone: Generating Rimentioning

confidence: 96%

“…3). The derivatives of 24-desmethylrifamycin B: 24-desmethylrifampicin and 24-desmethylrifamycin S, were tested against MDR strains of M. tuberculosis, where the activity was found to be 10 times better than the existing commercially available rifampicin [19].…”

Section: Stepping Stones For Generation Of 24-desmethylrifampicinmentioning

confidence: 99%

Synthetic Biology in Action: Developing a Drug Against MDR-TB

et al. 2014

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The amalgamation of the research efforts of biologists, chemists and geneticists led by scientists at the Department of Zoology, University of Delhi has resulted in the development of a novel rifamycin derivative; 24-desmethylrifampicin, which is highly effective against multi-drug resistant (MDR) strains of Mycobacterium tuberculosis. The production of rifamycin analogue was facilitated by genetic-synthetic strategies that have opened an interdisciplinary route for the development of more such rifamycin analogues aiming at a better therapeutic potential. The results of this painstaking effort of nearly 25 years of a team of students and scientists led by Professor Rup Lal have been recently published in the Journal of Biological Chemistry (www.jbc.org/content/289/30/21142. long). This strategy can now find applications for developing newer rifamycin analogues that can be harnessed to overcome the problem of MDR, extensively drug resistant (XDR) and totally drug resistant (TDR) M. tuberculosis.

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“…A programmable antibiotic technique selectively targets the bacteria which harbor the resistant strains while leaving other microbes alone, which wipe out the bad bugs at once. 3 They succeeded by instructing a bacterial enzyme "Cas9" to target the particular DNA sequence and cut it up. This approach leaves the microbial community intact and can keep the resistance in check and prevent certain type of secondary infections, eliminating the two hazard associated with treatment by classical antibiotics.…”

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Novel Approaches to Target the Antibiotic Resistance in Short Term

Kaushal¹

2017

JBMOA

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SummaryOne of the biggest threats to global health today is antibiotic resistance. There is a big concern that what is being done to combat this. Because bacteria develop antibiotic resistance faster as compared to the new development of antibiotics which takes years in its development.Antibiotic resistance is a challenge in the treatment of diseases today, as bacteria continuously mutate and develop resistance against multiple drugs design to kill them, turning them in to superbugs. Most commonly Gram negative bacteria gain the resistance to multiple antibiotics, no new drug will be available to treat these infections in near future e.g. carbapenem-resistant Enterobacteriaceae. WHO revealed that gram negative bacteria are frequently resistant to antibiotics in the 12 families of bacteria. The main contributing factor to increased drug resistance is permeability barrier caused by the outer membranes of bacteria.Synergistic use of antibiotics with FDA approved non-antibiotics is a novel approach which enable to breach the outer membrane barrier. In this innovative strategy non-antibiotic compounds boost the effectiveness of drugs. Anti-diarrheal medication loperamide enhance the effectiveness of eight different antibiotics. Minocycline with tetracycline along with drug benserazide increases the antibiotic activity against Pseudomonas aerogenosa, a causative agent of hospital acquired infections. Polymixin is known as effective drug against K. pneumonae, P. aerogenosa and Acinetobacter baumannii, plasmid transferable gene mcr-1 was discovered to create resistance to polymixin-E in 2015.Different combinations have been tried to increase the effectiveness. Without new antibiotics in near future, we must explore innovative approaches to preserve the clinical utility of important last-line antibiotics such as the polymyxins. A team of five researchers and clinicians in Singapore led by Dr Desmond Heng, ICES Institute of Chemical and Engineering Sciences and NUH National University Hospital have discovered new ways to use a combination of four new drugs formulations that are each made up of three different antibiotics to fight against the respiratory system infections and antibiotic resistant superbugs. These drugs are effective against Pseudomonas aerogenosa and Klebsiella pneumoniae. These formulations kill bacteria five times more effectively than antibiotics used for treating respiratory system infection these days.Researchers of Rockefeller University and their collaborators are working for smarter antibiotics. A programmable antibiotic technique selectively targets the bacteria which harbor the resistant strains while leaving other microbes alone, which wipe out the bad bugs at once. 3They succeeded by instructing a bacterial enzyme "Cas9" to target the particular DNA sequence and cut it up. This approach leaves the microbial community intact and can keep the resistance in check and prevent certain type of secondary infections, eliminating the two hazard associated with treatment by classical antibiotics. In the ...

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Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity against Rifampicin-resistant Mycobacterium tuberculosis

Cited by 45 publications

References 43 publications

Genetics and Genomics of the Genus Amycolatopsis

Genetics and Genomics of the Genus Amycolatopsis

Synthetic Biology in Action: Developing a Drug Against MDR-TB

Novel Approaches to Target the Antibiotic Resistance in Short Term

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