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Rapamycin and Easter Island

30 domingo Oct 2016

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rapanui

Rapa Nui (Easter Island) is situated in the southeastern Pacific Ocean, 163 km2, population 6.600 residents. Easter Island is famous for its 887 extant monumental statues, called moai, created by the early Rapa Nui people. Is a volcanic high island, dominated by hawaiite and basalt, the climate is classified as a tropical rainforest climate (Af) that borders on a humid subtropical climate.

A streptomycete was isolated from an Easter Island soil sample and found to inhibit Candida albicans, Microsporum gypseum and Trichophyton granulosum. The antibiotic-producing microorganism was characterized and identified as Streptomyces hygroscopicus. The antifungal principle was extracted with organic solvent from the mycelium, isolated in crystalline form and named rapamycin.

jensen-hl-actinomyces-2

Stresptomyces hygroscopicus  (Actenomyces hygroscopicus synonimus) is a bacterial species in the genus Streptomyces. It was first described by Hans Laurits Jensen in 1931. He was born in Graese, he came under the influence of Professor Weis in the Department of Plant Physiology at the Agricultural University in Lyngby, Denmark. His growing interest in soil microbiology. Main terms to his work have been supplied by actinomycetes, coryneform bacteria, and both free-living and symbiotic nitrogen fixing bacteria.

Scientific classification

  • Kingdom: Bacteria
  • Phylum: Actinobacteria
  • Class: Actinobacteria
  • Order: Actinomycetales
  • Family: Streptomycetaceae
  • Genus: Streptomyces
  • Species: hygroscopicus
  • Subspecies: hygroscopicus angustmyceticus, S. hygroscopicus decoyicus, S. hygroscopicus glebosus, S.hygroscopicus hygroscopicus, S. hygroscopicus ossamyceticus

 

Sirolimus, also known as rapamycin, is a macrolide, is used in medicine to prevent organ transplant rejection and to treat lymphangioleiomyomatosis.

  • Was isolated for the first time in 1972 by Suren Sehgal and colleagues from samples of Streptomyces hygroscopicus found on Easter Island. Sirolimus was initially developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent inmunosuppresive and antiproliferative properties due to its ability to inhibit mTOR
  • In the 1980s, found to have anticancer activity although the exact mechanism of action remained unknown until many years later.
  • Rapamycin was also it was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name.

mTOR  inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR). One of the most promising antiaging mechanisms was discovered by accident. In 2001 biologist Valter Longo of the University of Souther Calirfornia went away for a weekend and forgot to feed yeast cells that he was using in an experiment. He was surprised to discover that starving them completely for a time made them live longer than usual. The reason, he learned, lay in a cascade of molecular actions usually referred to by the enzyme at its center, which is called mTOR.

This pathway was originally discovered years earlier thanks to a drug called rapamycin, which was found in soil bacteria. The drug, scientists learned, affected a mayor pathway regulation growth and division in the cell, like the circuit breaker in a tiny factory. Researchers named the path mTOR because it is a “mechanistic target of rapamycin”. When mTOR is activated, the “factory” (that is, the cell)

  • producing new proteins,
  • growing
  • and ultimately dividing.

When mTOR is bloked, suchs as by rapamycin cell growth and replication slow down or stop. This is why rapamycin has been effective as an immunosuppressor to protect transplanted organs and more recently as a cancer therapy; these conditions involve runaway cell division.

Silorimus inhibits IL-2 and other cytokines receptor-dependent signal transduction mechanisms, via action on mTOR, and thereby blocks activation of T and B cells. The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tracrolimus. The sirolimus-FKBP12 complex inhibits the mTOR. Target Of Rapamycin,  pathway by directly binding to mTOR Complex 1 (mTORC1). mTOR  has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP.

Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump. It has elinimation half-life of 57-63 hours. The byosynthesis of the rapamycin core is accomplished by a type 1 polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three myltienzymes, Rap A, Rap B, Rap C, which contain a total of 14 modules. Then, the linear polyketide is modified by the NRPS, Rap P, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, pherapamycin.

When dosed appropriately, sirolimus can enhance the immune response to tumor targeting or otherwise promote tumor regression in clinical trials. Sirolimus seems to lower the cancer risk in some transplant patients. It was shown to inhibit the progression of dermal Kaposi´s sarcoma in patients with renal transplants. Other mTOR   inhibitors, such as temsirolimus or eversolimus, are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma.

A combination therapy of doxorubicin and sirolimus has been shown to drive AKT-positive lymphomas into remission in mice. Sirolimus blocks AKT signaling and the cells lose their resistance to the chemotherapy. Bcl-2-positive lymphomas were completely resistant to the therapy; eIF4E-expressing lymphomas are not sensitive to sirolimus.

mtor

mTOR  inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs), Mtor  regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes:  mTOR1  and mTOR2.  The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

Many human tumors occur because of dysregulation of mTOR signaling, and can conferhigher susceptibility to inhibitors of mTOR. Deregulations of multiple elements of the mTOR pathway, like P13K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1, and eIF4E overexpression have been related to many types of cancers. Therefore, mTOR is an interesting therapeutic target for treating multiple cancers, both the mTOR inhibitors themselves or in combination with inhibitors of other pathways.

 

Relation links:

  • Rapamycin

http://www.nature.com/nri/journal/v15/n10/box/nri3901_BX1.html

  • mTOR

https://www.youtube.com/watch?v=hbWUkArdptA

 

Bibliography:

  • Wikipedia
  • Jensen, HL (1931) “Contributions to our knowledge of actinomycetales” Biodiversity Heritage Library.
  • Vézina,C; Kudelski,A; Sehgal, S N (1975) “Rapamycin (AY-22,989), a new antigungal antibiotic. I. Taxonomuy of the producing streptomycete and isolation of the active principle”. The Journal of Antibiotics 28(10): 721-726.
  • Valter Long, Fabricio,P; Pozza, F; Plethcer,S; Gendrom, C.M; Longo, VD (2001) “Regulation of Logevity and Stross Resistence by Sch9 in Yeast”.
  • Chan S (2004) “Targeting the mmammalian target of rapamycin (mTOR): a new approach to treating cancer”. Br J Cancer 91(8)1420-4.
  • Wendel HG, De Stanchina E, Fridman JS, et al (2004) “Survival signaling by Akt and Eif4e in oncogenesis and cancer therapy”. Nature 428 (6980):332-7.Science Daily.
  • Novak, Kristine (2004) “Therapeutics: Means to an end” Nature Reviews Cancer 4:332.
  • Mayo Clinic Researches (2009) “Formulate Treatment Combination Lethal To Pancreatic Cancer Cells” Science, 292 (5515): 288-290. Doi:10//26/science.
  • Meric-Gernstam, F; Gonzalez-Angulo, A.M. (2009) “Targeting the Mtor Signaling Network for Cancer Therapy”. Journal of Clinical Oncology. 27 (13):2278-87.
  • Populo, Helena; Lopez, José Manuel; Soarez, Paula (2012) “The mTOR Signaling Patway in Human Cancer”. International Journal of Molecular Sciences.13 (12): 1886-918.
  • Bill Gifford (September  2016) “Will defeat aging”. Scientific American 58-60.
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Knudson hypothesis: Tumor Suppressor Gene

19 miércoles Oct 2016

Posted by in cáncer, CIENCIA

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knudson-hypotesis

The hypothesis: that cancer is the result of accumulated mutations to a cell´s DNA. It was first proposed by Carl O. Nordling in 1953, and later formulated by Alfred G. Knudson in 1971.

The multi-mutation theory on cancer was proposed by Nordling in the British Journal of Cancer in 1953: “the outbreak of cancer requires the accumulations of six consecutive mutations”. Knudson performed a statistical analysis on cases of retinoblastoma, a tumor of the retina that occurs both as an inherited disease and sporadically.

Knudson suggested that multiple “hits” to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the first insult was inherited in the DNA, and any second insult would rapidly lead to cancer. In non-inherited retinoblastoma, two “hits” had to take place before a tumor could develop, explaining the age difference.

It was later found that:

  • carcinogenesis (development of cancer)
  • depended both on the activation of proto-oncogenes (genes that stimulate cell proliferation) and on the desactivation of tumor suppressor genes (TSG), which are genes that keep proliferation in check.
  • Knudson´s hypothesis refers specifically, however, to the heterozygosity of tumor suppressor genes. A mutation in both alleles is required, as a single functional TSG is usually sufficient.

Tumor suppressor genes act as “brakes” to stop cells before they can travel down the road to cancer. A loss of function mutation in these genes can be disastrous. Some of these genes are involved in DNA repair processes, which help prevent the accumulation of mutations in cancer-related genes. Tumor suppressor genes act as “brakes” to stop cells in their tracks before they can take the road to cancer. Given this situation, loss of tumor suppressor gene function can be disastrous, and it often puts once-normal cells on the fast track to disease.

 

 

Knudson hypothesis (The Two-Hit Hypothesis or Multiple-hit hypothesis)

It was first proposed by geneticist Alfred Knudson in 1971. The two-hit hypothesis arose of out Knudson´s interest in the genetic mechanisms underlying retinoblastoma, a childhood form of retinal cancer.

Knudson studied 48 patients with retinoblastoma who had been admitted to the hospital between 1944 and 1969. Suggested that:

  1. An individual could inherit a germ-line mutation but not have disease
  2. While the majority of children with an affected parent had bilateral tumors (25-30%) some had only unilateral tumors (10-15%).

 

Furthermore, he determined that approximately 60% of retinoblastoma cases in the U.S. were unilateral and were not associated with a family history of the disease.

 

HEREDITARY:   Bilateral (25-30%), Unilateral (10-15%) : 35-45%

NONHEREDITARY:                             Unilateral (55 -65%): 55-65%

BILATERAL:                                                                                   25-30%

UNILATERAL:                                                                               70-75%

 

Knudson examined the age at which the children in these two groups were diagnosed with retinoblastoma: without an inherited mutation, the same cell would need to accumulate two mutations- one in each allele of the gene-and this process would be much slower.

The rate of diagnosis for unilateral nonhereditary retinoblastoma was delayed relative to that bilateral cases and showed a curve consistent with a two-mutation process.

Knudson concluded that retinoblastoma was caused by two mutations: one in each copy of a single tumor suppressor gene (RB1). He also estimated that each of the two mutations would occur at a rate of 2 x 10 -7 per year. Patients who inherited an RB1 mutation would develop tumors earlier, inherit a mutation would almost always be affected by a single tumor. This statement, which Knudson called the two-mutation hypothesis, is now known as the two-hit hypothesis.

“Loss of heterozygosity” is often used to describe the process that leads to the inactivation of the second copy of a tumor suppressor gene. A heterozygous cell receives a second hit in its remaining functional copy of the tumor suppressor gene, thereby becoming homozygous for the mutated gene. Mutations that inactivate tumor suppressor genes, called loss-of-function mutations, are often point mutations or small deletions that disrupt the function of the protein that is encoded by the gene; chromosomal deletions or breaks that delete the tumor suppressor gene; or instances of somatic recombination during which the normal gene copy is replaced with a mutant copy.

Knudson developed the two-hit hypothesis long before the human genome was sequenced, and the RB1 gene was itself discovered in 1986. Researches notice that: some cases of retinoblastoma were associated with a deletion of chromosome band 13q14 and then used restriction fragment length polymorphism (RFLP) analysis to isolate the RB1 gene (Friend et al 1986).

RB1 function has been shown to be inactivated by four distinct mechanisms:

  1. Genetic inactivation
  2. Sequestration of the RB1 –encoded protein by viral oncoproteins
  3. Phosphorylation of the RB1 –encoded protein
  4. And degradation of the RB1 –encoded protein

 

RB1 is one gene among a growing list of tumor suppressor genes. According to the American Cancer Society (2005): at least 30 different tumor suppressor genes have been identified:

  • RB1 Retinoblastoma: cell division, DNA replication, cell death
  • TP53 Li-Fraumeni syndrome (brain tumors, sarcomas, leukemia):cell division, DNA repair, cell death
  • CDKN2A Melanoma: cell division, cell death
  • APC Colorectal cancer (due to familial polyposis): cell division, DNA damage, cell migration, cell adhesion, cell death.
  • MLH1, MSH2, MSH6 Colorectal cancer (without polyposis): DNA mismatch repair, cell cycle regulation
  • BRCA1, BRCA2 Breast and/or ovarian cancer: Repair of double-stranded DNA breaks, cell division, cell death
  • WT1, WT2 Wilm´s tumor: Cell division, transcriptional regulation
  • NF1, NF2 Nerve tumors (including brain): RAS-mediated signal transduction, cell differentiation, cell division, developmental processes.
  • VHL Kidney cancer: Cell division, cell death, cell differentiation, response to cell stress.

 

Alfred George Knudson, Jr (1922-2016) was an American physician and geneticist specializing in cancer genetics. Knudson was born in Los Angeles, California in 1922, his M.D. from Columbia University in 1947 and his Ph.D. from California Institute of Technology in 1956. From 1970 to 1976, Knudson served as the Dean of Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston in the Texas Medical Center. He has been affiliated with the Fox Chase Cancer Center in Philadelphia from 1976 until his death in 2016.

Knudson is best known for his “two-hit hypothesis” explaining the incidence of hereditary cancers, such as retinoblastoma.

Our increasing knowledge of tumor suppressor gene function will continue to enhance our ability to diagnose and more effectively treat cancers at the molecular level in the years to come.

Bibliography:

  • Wikipedia
  • American Cancer Society 2005
  • British Journal of Cancer 1953 7, 68–72. doi:10.1038/bjc.1953.8 http://www.bjcancer. com … A New Theory on the Cancer-inducing Mechanism. C O Nordling
  • Nature Publishing Group Knudson, A. “Two genetic hits (more or less) to cancer. Nature Reviews Cancer 1, 160 – 2001.

 

Relation Links:

 

Tumor Suppressor Genes (Retinoblastoma and the two hit hypothesis, p

 

 

Dr. Al Knudson discusses the «Two-Hit» Theory

 

 

 

Nobel Prize & Autophagy: Yoshinori Ohsumi

12 miércoles Oct 2016

Posted by in Célula, CIENCIA

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autophagy

Autophagy has been known for over 50 years bus its fundamental importance in physiology and medicine was only recognized after Yoshinori Ohsumi´s paradigm-shifting research in the 1990´s. For his discoveries, he is awarded this year´s Nobel Prize in physiology or medicine.

For pioneering the molecular elucidation of autophagy, an essential intracelular, degradation system and when disordered, is linked to many diseases including neurodegeneration, cancer, and infection.

Dr. Yoshinori Ohsumi was born in Fukuoka in 1945. In 1963, he entered to The Univ. of Tokyo, and then he chose decisively to follow molecular biology as the path of his future. As a graduate student, Dr. Oshumi studied the initiation mechanism of E. coli ribosome and then action of colicin E3, which inhibits the translation of E.coli cells by binding to its receptor. Near the end of 1974, he enrolled in Rockefeller Univ., to study under Dr. G. M. Edelman. First Dr. Oshumi worked on in vitro fertilization in mice, then switched to work on the mechanism of initiation of DNA replication using yeast, which introduced him to yeast research. Dr. Ohsumi returned to Japan at the end of 1977, and worked as an assistant professor under Prof. Y. Anraku, at the Faculty of Science. The Univ. of Tokyo. Dr Ohsumi decided to take up the study of the yeast vacuolar membrane.

Dr. T. Yoshinori and N. Mizushima in his lab started studies on ATG genes in mammals and a student also worked on plant, proving studies on ATG system is well conserved in higher eukaryotes. However up to now, Dr. Ohsumi has focused on dissection of the molecular mechanism of the ATG proteins in yeast.

Autophagy is a process by which cellular components are captured into organelles called autophagosomes and then brought to the lysosome or vacuole to be broken down and recycled for other uses. It frequently comes into play during starvation, allowing cells to survive periods of privation.

He has:

  • Identified most of the proteins and pathways involved in the process
  • Demonstrated how they are regulated by proteins that sense cells metabolic states
  • Started to outline the fine mechanistic details of autophagosome formation in yeast

“The vacuole was thought to be just a garbage can in the cell, and nor very may people were interested in its physiology, so I thought it would be good to study transport in the vacuole because I would not have much competition. Another reason I chose study vacuole physiology is that, while I was in Dr. Edelman’s lab. We had tried to isolate nuclei from yeast cells, and along the way we discovered that it was easy to get pure preparations of vacuoles. Using these preparations, I was able to find many active transport systems in the vacuolar membrane, including the vacuolar-type ATPase that pumps protons into the vacuole”. (1992, The Rockefeller University Press).

“I had a very simple idea: the vacuole can be detected under the light microscope, and it was already considered to be a garbage compartment where protein degradation takes place. So, I thought it would be easy to observe morphological change in the vacuoles of cells that were undergoing lots of degradation. Cell differentiation processes require lots of protein degradation, so I looked at vacuolar proteinase-deficient mutants, which cannot sporulate as normal cells do under nitrogen-starvation conditions, to see if I could observe any changes to vacuolar structure”.

The Nobel Assembly at Karolinska Institute has decided to award the 2016 Nobel Prize in Physiology or Medicine to Yoshinori Oshumi for his discoveries of mechanisms for autophagy (2016-10-03):

This year´s Nobel Laureate discovered and elucidated mechanisms underlying autophagy, a fundamental process for degrading and recycling cellular components.

Summary

The word autophagy originates from the Greek words auto-, meaning “self”, and phagein, meaning “to eat”. Thus, autophagy denotes “self eating”. This concept emerged during the 1960´s, when researches first observed that the cell could destroy its own contents by enclosing it in membranes, forming sack-like vesicles that were transported to a recycling compartment, called the lysosome, for degradation.  Brilliant experiments in the early 1990´s, Yoshinori Ohsumi used baker´s yeast to identify genes essential for autophagy in yeast and showed that similar sophisticated machinery is used in our cells. Importance of autophagy in many physiological processes, such as in the adaptation to starvation or response to infection. Mutations in autophagy genes can cause disease, and the autophagic process is involved in several conditions cancer and neurological disease.

Degradation- a central function in all living cells

In the mid 1950´s scientists observed a new specialized cellular compartment, called an organelle, containing enzymes that digest proteins, carbohydrates and lipids. This specialized compartment is referred to as a “lysosome” and functions as a workstation for degradation of cellular constituents. Further biochemical and microscopic analysis revealed a new type of vesicle transporting cellular cargo to the lysosome for degradation. Christian de Duve, the scientist behind the discovery of the lysosome, coined the term autophagy, “self-eating”, to describe this process. The new vesicles are named autophagosomes.

During the 1970´s and 1980´s researchers focused on elucidating another system used to degrade proteins, namely the “proteasome”. Aaron Ciechanover, Avram Hershko and Irwin Rose were awarded the 2004 Nobel Prize in Chemistry for “the discovery of ubiquitin-mediated protein degradation”.

A groundbreaking experiment

Ohsumi reasoned that if he could disrupt the degradation process in the vacuole while the process of autophagy was active, then autophagosomes should accumulate within the vacuole and become visible under the microscope. He therefore cultured mutated yeast lacking vacuolar degradation enzymes and simultaneously stimulated autophagy by starving the cells. The results were striking.

Autophagy genes are discovered

Ohsumi exposed the yeast cells to a chemical that randomly introduced mutations in many genes, and then he induced autophagy. His strategy worked, identified the first genes essential for autophagy. The results showed that autophagy is controlled by a cascade of proteins and protein complexes, each regulating a distinct stage of autophagosome initiation and formation. He studied thousands of yeast mutants and identified 15 genes that are essential for autophagy and the function of the proteins encoded by key autophagy genes. He delineated how stress signals initiate autophagy and the mechanism by which proteins and protein complexes promote distinct stages of autophagosome formation.

Autophagy- an essential mechanism in our cells

Thanks to Ohsumi, autophagy controls important physiological functions where cellular components need to be degraded and recycled. Autophagy can rapidly provide fuel for energy and building blocks for renewal of cellular components, and is therefore essential for the cellular response to starvation and other types of stress.

  • After infection, autophgy can eliminate invading intracellular bacteria and viruses.
  • Autophagy contributes to embryo development and cell differentiation
  • Cells also use autophagy to eliminate damaged proteins and organelles, a quality control mechanism that is critical for counteracting the negative consequences of aging.

Disrupted autophagy has been linked to:

  • Parkinson´s disease
  • Type 2 diabetes

Mutations in autophagy genes can cause genetic disease. Disturbances in the autophagic machinery have also been linked to cancer. Research is now ongoing to develop drugs that can target autophagy in various diseases.

Biography Yoshinori Ohsumi

  • 2016-present　　Professor, Institute of Innovative Research, Tokyo Institute of Technology
  • 2014-present　　Honorary Professor, Tokyo Institute of Technology
  • 2010-2016　　　　Professor, Frontier Research Center, Tokyo Institute of Technology
  • 2009-2010　　　　Professor, Advanced Research Organization, Integrated Research Institute, Tokyo Institute of Technology
  • 2004-2009　　　　Professor, The Graduate University for Advanced Studies [SOKENDAI]
  • 1996-2009　　　　Professor, Department of Cell Biology, National Institute for Basic Biology
  • 1988-1996　　　　Associate Professor, Department of Biology, College of Arts and Sciences, The University of Tokyo
  • 1986-1988　　　　Lecturer, Department of Biology, Faculty of Science, The University of Tokyo
  • 1977-1986　　　　Research Associate, Department of Biology, Faculty of Science, The University of Tokyo, with Prof. Yasuhiro Anraku
  • 1974-1977　　　　Postdoctoral Fellow, Rockefeller University with Prof. Gerald M. Edelman
  • 1972-1974　　　　Research Fellow, Department of Agricultural Chemistry, Faculty of Agriculture, The University of Tokyo
  • 1967-1972　　　　Graduate Student, Department of Biochemistry, College of Arts and Sciences, The University of Tokyo, with Prof. Kazutomo Imahori
  • 1963-1967　　　　Undergraduate Student, Department of Basic Science, College of Arts and Sciences, The University of Tokyo Awards

Key publications

  • Takeshige, K., Baba, M., Tsuboi, S., Noda, T. and Ohsumi, Y. (1992). “Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction”. Journal of Cell Biology 119, 301-311
  • Tsukada, M. and Ohsumi, Y. (1993). “Isolation and characterization of autophagy-defective mutants of Saccharomyces cervisiae”. FEBS Letters 333, 169-174
  • Mizushima, N., Noda, T., Yoshimori, T., Tanaka, Y., Ishii, T., George, M.D., Klionsky, D.J., Ohsumi, M. and Ohsumi, Y. (1998). “A protein conjugation system essential for autophagy”. Nature 395, 395-398
  • Ichimura, Y., Kirisako T., Takao, T., Satomi, Y., Shimonishi, Y., Ishihara, N., Mizushima, N., Tanida, I., Kominami, E., Ohsumi, M., Noda, T. and Ohsumi, Y. (2000). “A ubiquitin-like system mediates protein lipidation” Nature, 408, 488-492

Related Links

  • Yoshinori Ohsumi wins medicine Nobel Prize

https://www.youtube.com/watch?v=81W5OwTdxjw

  • Autophagy

Resistencia de las bacterias a los antibióticos

01 sábado Oct 2016

Posted by in Bioquímica, CIENCIA

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antibiotic_resistance_es

La llegada de los antibióticos ha sido una gran herramienta para las enfermedades bacterianas pero no la definitiva. La mutación espontánea de una bacteria haciéndose resistente al medicamento y la multiplicación, no es suficiente para explicar la resistencia tan elevada. La mutación de un gen ocurre una vez cada 10 a 1.000 millones de divisiones celulares, existen mecanismos de transferencia de transmisión genética en las bacterias que tienen que ser considerados como posibilidades.

 

El informe de la Organización Mundial de la Salud (OMS): “Antimicrobial resistance: global reporto n surveillance” la resistencia está afectando a muchos agentes infecciosos distintos, pero se centra en la resistencia a los antibióticos en siete bacterias de infecciones comunes graves: la septicemia, la diarrea, la neumonía, infecciones urinarias o la gonorrea.

Los principales puntos del informe son:

  • Resistencia a los antibióticos carbapenémicos: Klebsiella pneumoniae (bacteria intestinal), pneumoniae (infecciones nosocomiales- neumonías, las septicemias, las infecciones de los recién nacidos, pacientes ingresados en unidades de cuidados intensivos).
  • Resistencia a las fluoroquinolonas: tratamiento de las infecciones urinarias por coli.
  • Resistencia a las cefalosporinas: tratamientos de gonorrea.
  • Resistencia a los antibióticos en enfermedades de larga duración aumentando el riesgo de muerte. Staphylococcus aureus.

 

Datos de resistencias por regiones de la OMS

  • Región de África: coli, S. aureus
  • Región de las Américas: E.coli, K.pneumoniae, S.aureus
  • Región del Mediterráneo Oriental: penumoniae, S.aureus
  • Región de Europa: pneumoniae, S.aureus
  • Región de Asia Sudoriental: E.coli, K.pneumoniae
  • Región del Pacífico Occidental: E.coli, K. pneumoniae, S.aureus

 

 

 

 

Cronología de la resistencia a antibióticos (Wikipedia)

Antibiótico                        Descubrimiento       Introducción      Resistencia

  • Sulfonamidas                 1932                          1936                    1942
  • Betalactámicos              1928                          1938                    1945
  • Aminoglucósidos           1943                          1946                    1946
  • Cloranfenicoles             1946                          1948                    1950
  • Macrólidos                       1948                          1951                    1955
  • Tetraciclinas                   1944                          1952                     1950
  • Rifamicinas                     1957                          1958                    1962
  • Glucopéptidos                 1953                          1958                    1960
  • Quinolonas                      1961                           1968                    1968
  • Estreptograminas         1963                           1998                    1968
  • Oxazolidinonas              1955                            2000                    2001
  • Lipopéptidos                   1986                           2003                   1987
  • Fidaxomicina                  1948                           2011                     1977
  • Diarilquinolina               1997                           2012                    2006

 

Mecanismos de resistencia

El antibiótico se convierte en el primer factor de selección. La resistencia no es igual para toda la población, con diferencias morfológicas o bioquímicas, puede haber susceptibilidades totalmente diferentes, incluso en dosis bajas del antibiótico. Las resistencias no aparecen tan difundidas en Gram positivas, ya que no son capaces de incorporar plásmidos. En el caso de Gram negativos la resistencia se disemina ampliamente y se transfiere con facilidad.

1.Resistencias cromosómicas

Dan lugar a cambios estructurales, graduales, debidas a mutaciones en el proceso de replicación del ADN, por ejemplo a la estreptomicina, rifampicina, ácido nalidíxico y la vancomicina.

2. Resistencias transferibles

La bacteria adquiere información genética transferida de otra bacteria, que es resistente.  Puede prevenir ese material de microorganismos resistentes o de bacterias que producen antibióticos, a través de mecanismos de picking-up y recombinación de genes.

Según la “hipótesis del reservorio” (Sundin and Bender, 1996; Hayward and Griffin, 1994; van der Waaji et al, 1971; Stobbering et al, 1999), cierta concentración umbral de antibiótico es necesaria para inducir y luego mantener resistencias, sería aquella capaz de seleccionar bacterias, aún saprófitas. La supresión del uso del antibacteriano al que los microorganismos han desarrollado resistencia, bebería generar un fenómeno inverso, a través del cual, la población resistente, lentamente dejaría lugar a cepas susceptibles.

 

Mecanismos de transferencia de resistencias

  • Plásmidos: porciones circulares de ADN extracromosómico que puede estar codificado para resistencia a un determinado antibiótico. Cuando codifican resistencias se los denomina plásmidos R.
  • Transposones: genes saltarines, cadenas cortas de ADN que saltan de cromosoma a plásmido, en uno u otro sentido, entre plásmidos o entre plásmidos y bacteriófagos.
  • Integrones y casetes genéticos: se recombinan en un sitio específico y codifican resistencias a un solo antibiótico, junto con los transposones son los que más actúan en la adquisición de resistencias por parte de los plásmidos.

Mecanismos de resistencia

  • Inactivación enzimática: como en el caso de las betalactamasas, la bacteria la inactiva sin poder actuar.
  • Impermeabilidad de la membrana o pared celular: por ejemplo modificaciones en las porinas, lo que repercute en resistencias de bajo nivel a diversos antimicrobianos.
  • Expulsión por mecanismos activos del antibiótico: por ejemplo las resistencias a las tetraciclinas.
  • Modificación del sitio blanco del antibiótico en la bacteria: en algunos casos disminución de la afinidad del receptor por la molécula antimicrobiana.

 

Bacterias resistentes en la población humana

1.Infecciones hospitalarias 

  • Estafilococos meticilino-resistentes
  • Enterobacter cloacae
  • Enterococos
  • Pseudomonas aeruginosa

 2.Población urbana o rural

  • Streptococcus pneumoniae
  • Streptococcus pyogenes
  • Escherichia coli
  • Mycobacterium tuberculosis
  • Neisseria gonorrheae
  • Salmonella
  • Campylobacter

 

Bacterias animales en la población humana

  • Escherichia coli
  • Salmonella typhimurium
  • Campylobacter

Está ligado a eventuales transferencias entre especies,  humanos y animales. En EE.UU más del 70% de los antibióticos producidos se usan para alimentación animal (pollos, cerdos y vacas) en ausencia de enfermedad.

 

 

Instrumentos para hacer frente a la resistencia de antibióticos (OMS)

          Las personas

  • Utilizar solo antibióticos bajo prescripción médica
  • Completar el tratamiento prescrito
  • No dar los antibióticos a otras personas, ni utilizar los sobrantes

         Profesional sanitario y farmacéutico

  • Mejorar la prevención y el control de las infecciones
  • Prescribir y dispensar antibióticos solo cuando son necesarios
  • Prescribir y dispensar antibióticos adecuados para la enfermedad en cuestión

        Planificadores de políticas

  • Reforzar el seguimiento de la resistencia y capacidad de laboratorio
  • Regular el uso apropiado del medicamento

        Planificadores de políticas y la industria

  • Fomentar innovación y desarrollo de nuevos instrumentos
  • Promover cooperación y el intercambio de información entre todas las partes 

 

Links relacionados: 

  • Antibióticos Ministerio de Sanidad

http://www.antibioticos.msssi.gob.es/home.html 

  • Resistencia a los antibióticos

https://www.youtube.com/watch?v=5Mb0ICsd3L8