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Posts Tagged ‘antibacterial resistance’


New antibacterials against resistant strains

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

WCK ? , WCK Series by Wockhardt for treating the bacterial infection

by DR ANTHONY MELVIN CRASTO Ph.D

Sulfuric acid, mono[(1R,​2S,​5R)​-​7-​oxo-​2-​[[[(2S)​-​2-​pyrrolidinylmethoxy]​amino]​carbonyl]​-​1,​6-​diazabicyclo[3.2.1]​oct-​6-​yl] ester

364.37

C12 H20 N4 O7 S

CAS 1452459-04-9

PATENTS, WO 2015079329, WO 2015079389 , WO 2015063714, US 20130225554

Emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating bacterial infections. One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistant. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have reviewed novel approaches to developing new antibiotics. However, the development of new antibacterial agents is a challenging task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have reviewed the challenges in discovery of antibacterial agents.

Several compounds have been described in the prior art for use in treatment of bacterial infections (for example, see Patent Application Nos. PCT/IB2012/054296, PCT/IB2012/054290, US20130225554, PCT/US2010/060923, PCT/EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/EP2009/056178, PCT/US2009/041200, PCT/US2013/034562, PCT/US2013/034589, PCT/IB2013/053092 and PCT/IB2012054706). However, there remains a need for potent antibacterial agents for preventing and/or treating bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.

 

PATENT

WO 2015079329

https://encrypted.google.com/patents/WO2015079329A2?cl=en

 

 

 

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Antibiotic Resistance

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Resistance Gene to Last Line of Antibiotic Defense Has Emerged

http://www.genengnews.com/gen-news-highlights/resistance-gene-to-last-line-of-antibiotic-defense-has-emerged/81252000/

Drug resistance can often emerge due to the selective pressure of antibiotic use on a microbial population. [NIAID]

 

Until recently, resistance to the polymyxin class of antibiotics—the last line of microbial defense—was thought to be highly improbable. However now, Chinese scientists have discovered a new gene, called mcr-1 that is widespread among Enterobacteriaceae, a large family of Gram-negative bacteria that include a variety of human pathogens, after taking samples from pigs and patients in South China.

“These are extremely worrying results. The polymyxins (colistin and polymyxin B) were the last class of antibiotics in which resistance was incapable of spreading from cell to cell. Until now, colistin resistance resulted from chromosomal mutations, making the resistance mechanism unstable and incapable of spreading to other bacteria,” explained co-author Jian-Hua Liu, Ph.D., a professor at the South China Agricultural University in Guangzhou, China. “Our results reveal the emergence of the first polymyxin resistance gene that is readily passed between common bacteria such as Escherichia coli and Klebsiella pneumoniae, suggesting that the progression from extensive drug resistance to pandrug resistance is inevitable.”

The investigators found the mcr-1 gene on plasmids within various bacterial strains, suggesting an alarming potential to spread and differentiate between diverse microbial populations.

The findings from this study were published recently in The Lancet Infectious Diseases through an article entitled “Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study.”

The researchers stumbled across the mcr-1 gene while performing routine testing of livestock for antimicrobial resistance on a pig farm in Shanghai. This prompted the researchers to collect bacteria samples from pigs at slaughter across four provinces, and from pork and chicken sold in 30 open markets and 27 supermarkets across Guangzhou between 2011 and 2014. Additionally, the scientists analyzed bacteria samples from patients presenting with infections at two hospitals in Guangdong and Zhejiang provinces.

What they found was troubling to say the least, as a high prevalence of the mcr-1 gene in E. coli was observed in isolates from animal (166 of 804) and raw meat samples (78 of 523). Moreover, the proportion of positive samples has been observed to be increasing from year to year.

The scientists also found that the transfer rate of the mcr-1 gene was very high between E. coli strains and that it has a strong potential to spread into other epidemic pathogenic bacterial species such asK. pneumoniae and Pseudomonas aeruginosa—making the rapid dissemination into humans very likely.

“Because of the relatively low proportion of positive samples taken from humans compared with animals, it is likely that mcr-1 mediated colistin resistance originated in animals and subsequently spread to humans,” noted senior author Jianzhong Shen, Ph.D., professor at the China Agricultural University in Beijing, China. “The selective pressure imposed by increasingly heavy use of colistin in agriculture in China could have led to the acquisition of mcr-1 by E. coli.”

The importance of selective pressure on this resistance gene becomes even more evident when considering the fact that China is one of the world’s largest users and producers of colistin for agriculture and veterinary use. Worldwide, the demand for colistin in agriculture is expected to reach almost 12,000 tons per year by the end of 2015, rising to 16,500 tons by 2021.

“The emergence of mcr-1 heralds the breach of the last group of antibiotics,” the authors stated. “Although currently confined to China, mcr-1 is likely to emulate other resistance genes such as blaNDM-1 and spread worldwide. There is a critical need to re-evaluate the use of polymyxins in animals and for very close international monitoring and surveillance of mcr-1 in human and veterinary medicine.”

 

Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study  

Yi-Yun Liu, Yang Wang, Timothy R Walsh, Ling-Xian Yi, Rong Zhang, James Spencer, et al.

DOI: http://dx.doi.org/10.1016/S1473-3099(15)00424-7      http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00424-7/abstract

Background

Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae.

Methods

The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli andKlebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model.

Findings

Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10−1 to 10−3 cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011–14, and 16 (1%) of 1322 samples from inpatients with infection.

Interpretation

The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as
NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria.

 

Colistin resistance: a major breach in our last line of defence

In hospital practice, clinicians have been buoyed by the recent development of new antibiotics active against multidrug resistant Gram-negative bacilli. However, recently approved antibiotics like ceftazidime-avibactam or ceftolozane-tazobactam do not provide activity against all Gram-negative bacilli, with notable gaps in their coverage, including the notorious New Delhi metallo-β-lactamase 1-producing organisms and many strains of carbapenem resistant Acinetobacter baumannii. For this reason, the polymyxins (colistin and polymyxin B) remain the last line of defence against many Gram-negative bacilli.
References
  1. The White House Office of the Press Secretary. FACT SHEET: Obama Administration Releases National Action Plan to Combat Antibiotic-Resistant Bacteria. https://www.whitehouse.gov/the-press-office/2015/03/27/fact-sheet-obama-administration-releases-national-action-plan-combat-ant. ((accessed Oct 20, 2015).)
  2. Walsh, F. Antibiotic resistance: Cameron warns of medical ‘dark ages’.http://www.bbc.co.uk/news/health-28098838. ((accessed Oct 20, 2015).)
  3. WHO. Antimicrobial resistance: global report on surveillance 2014. Wolrd Health Organization,Geneva; 2014http://www.who.int/drugresistance/documents/surveillancereport/en/. ((accessed Oct 20, 2015).)
  4. McKenna, M. CDC Threat Report: We will soon be in a post-antibiotic era. Wired. Sept 16, 2013;http://www.wired.com/2013/09/cdc-amr-rpt1/. ((accessed Oct 20, 2015).)
  5. Kumarasamy, KK, Toleman, MA, Walsh, TR et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study.Lancet Infect Dis. 2010; 10: 597–602
  6. Munoz-Price, LS, Poirel, L, Bonomo, RA et al. Clinical epidemiology of the global expansion ofKlebsiella pneumoniae carbapenemases. Lancet Infect Dis. 2013; 13: 785–796
  7. Falagas, ME, Karageorgopoulos, DE, and Nordmann, P. Therapeutic options for infections with Enterobacteriaceae producing carbapenem-hydrolyzing enzymes. Future Microbiol. 2011; 6: 653–666
  8. Halaby, T, Al Naiemi, N, Kluytmans, J, van der Palen, J, and Vandenbroucke-Grauls, CM.Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. Antimicrob Agents Chemother. 2013; 57: 3224–3229

 

https://www.reddit.com/r/science/comments/3tdyaz/emergence_of_plasmidmediated_colistin_resistance/

This is my second attempt at my first time contributing a link so hopefully this is the correct subreddit. This really highlights why research focused on discovery of novel antibiotics and resistance modifying agents is so important.  The article is summarized in the BBC: http://www.bbc.com/news/health-34857015

 

What a shame this isn’t getting any more attention in the news, antibiotic resistance is becoming more and more of a problem, and nobody is giving a fuck it seems. Colistin is used as a last defense against extensive resistant Gram-negative bacteria, and if resistance against it now also comes in a plasmid flavor, implications could be big.

 

Yes, the gene has been known for a fair amount of time but the fact it is now in plasmids that can easily transfect other bacteria is a bit disconcerting. Hopefully some of the new soil cultured classes of antibiotics make it into clinical settings soon.

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Important and timely

New Drug Approvals

 

Antimicrobials are medicines that kill or inactivate microbes, small disease-causing organisms. They include antibiotics, which are used against bacteria. After being exposed to an antimicrobial repeatedly, microbes can undergo changes that stop them being killed or inactivated by the treatments. This is known as antimicrobial resistance.

The European Medicines Agency is concerned about the development of antimicrobial resistance, particularly resistance to antibiotics. A well-known example of a bacterium that is resistant to a number of antibiotics is meticillin-resistant Staphylococcus aureus(MRSA), which has caused infections that are difficult to treat across the European Union (EU).

 

This problem is being made worse by the fact that few new antimicrobials have been authorised over the past few years. This may lead to infections becoming more difficult to treat in the future.

Antimicrobial resistance is a growing problem in humans and in animals. Resistance can also spread from animals to…

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Engineering Evil

Br J Biomed Sci. 2009;66(4):186-9.

In vitro activity of Inula helenium against clinical Staphylococcus aureus strains including MRSA.

Source

Department of Biological Sciences, Cork Institute of Technology, Cork, Ireland.

Abstract

The present study aims to investigate the bactericidal activity (specifically antistaphylococcal) of Inula helenium. The antimicrobial activity of the extract is tested against 200 clinically significant Irish Staphylococcus aureus isolates consisting of methicillin-resistant (MRSA) and -sensitive (MSSA) S. aureus using a drop test method and a microbroth dilution method. The antibacterial effect is evaluated by measuring the area of the inhibition zone against the isolates. Results proved I. helenium to be 100% effective against the 200 staphylococci tested, with 93% of isolates falling within the ++ and +++ groups. The minimum bactericidal concentration of I. helenium was examined on a subset of isolates and values ranged from 0.9 mg/mL to…

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ClinicalNews.Org

Contact: Angela Dansby aldansby@ift.org 312-782-8424 x127 Institute of Food Technologists

When cinnamon is in, Escherichia coli O157:H7 is out.  That’s what researchers at Kansas State University discovered in laboratory tests with cinnamon and apple juice heavily tainted with the bacteria.  Presented at the Institute of Food Technologists’ 1999 Annual Meeting in Chicago on July 27, the study findings revealed that cinnamon is a lethal weapon against  E. coli O157:H7 and may be able to help control it in unpasteurized juices.

Lead researcher Erdogan Ceylan, M.S., reported that in apple juice samples inoculated with about one million E. coli O157:H7 bacteria, about one teaspoon (0.3 percent) of cinnamon killed 99.5 percent of the bacteria in three days at room temperature (25 C).  When the same amount of cinnamon was combined with either 0.1 percent sodium benzoate or potassium sorbate, preservatives approved by the Food and Drug Administration, the E. coli were…

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