Antimicrobial resistance (AMR) is the ability of microorganisms that cause disease to withstand attack by antimicrobial medicines.
Although pathogenic mutations are random, environments where many antibiotics are used and germ transfer is quite common can accommodate selection for drug resistance quite well. Day cares and nursing homes are examples of such environments. Short generation times as well as frequent horizontal gene transfer also accounts for the rapid development of antibiotic resistance, particularly in the high risk environments mentioned previously.
- Pathogenic microbes are able to improve their chances of survival by random mutations which lead to resistance or immunity to antimicrobial agents. There are a few ways in which this can happen:
- Variations in surface proteins can alter the structure of the target protein of the antimicrobial, so that host antigens cannot recognize them. This is known as antigenic variation.
- Examples of pathogens that use this resistance mechanism include the malaria parasite Plasmodium falciparum andTrypanosoma brucei, the parasite responsible for African Sleeping Sickness.
- Evolution of new enzymes that can use the antimicrobial as a substrate can then break it down into a harmless form.
- Changes in metabolic pathways that are affected by antimicrobials can diminish their effect on the organism.
- The membrane can become less permeable to the antimicrobial, or the organism can increase the speed or efficiency of removing the antimicrobial.
- The use of probiotics is a treatment method that uses the "good" microbes to balance the mix of microbes in the body in order to promote mental health.
This is an awesome website about the evolution of antibiotic resistance (check out the animations).
Are there multiple ways for bacteria to acquire resistance?
Yes! Resistance can be acquired in different ways as detailed in this paper
. First let's look at how antibiotics inhibit bacterial functions:
1. Interference with cell wall synthesis - there are two primary types of antibiotics that interfere with or inhibit cell wall synthesis of the target bacteria: B-Lactam (Beta-lactam) and glycopeptide antibiotics
2. Inhibition of protein synthesis- e.g. tetracyclines block the aminoacyl site of the 30S ribosome which prevents tRNA from binding and therefore preventing protein synthesis
3. Interference with nucleic acid synthesis- e.g. quinolones are a group of antibiotics that inhibit topoisomerase II, an enzyme involved in DNA replication in bacterial cells
4. Inhibition of a metabolic pathway- e.g. growth factor analogs, like sulfanilamide, inhibit enzymatic activity in metabolic pathways such as the production of folic acid which is needed for the synthesis of purines and pyrimidines
5. Disruption of bacterial membrane structure- e.g. polymyxin B is a cyclic peptide antibiotic and increases the permeability of the cell membrane which causes cells to take up too much water and lyse; however, this antibiotic also affects kidney and nerve cells in humans.
So how can bacteria fight back against these attacks? Through mutations, bacteria can gain the ability to:
-produce enzymes that destroy the antibacterial drug: e.g. Bacteria can make Beta-lactamases that inhibit the Beta-lactam antibiotics such as penicillin. These are usually secreted by gram negative bacteria.
-prevent the drug from reaching its target through modification of efflux systems
-alter the drug’s target site: e.g. Staphylococcus aureus acquired a gene that resulted in a change of the penicillin binding protein on the outside of its cell wall making it resistant to Beta-lactams resulting in what we know today as MRSA.
-develop an alternative metabolic pathway that skirts the action of the drug
And how can these mutations spread throughout the bacterial population?
Through conjugation, transformation, and/or transduction these mutations can be transferred between bacteria. An important conclusion from this realization is that bacteria's ability to gain resistance in multiple ways allows for resistance to many different antibiotics.
Ways to Lower the Possibility/Slow Down the Development of Pathogenic Resistance:
Overuse of antibiotics is in reference to using antibiotics for something that is not treatable (like viral infections). Whereas misuse of antibiotics is the failure to take the antibiotic exactly as it is prescribed (ending a course of antibiotics early). When both of these occur, the antibiotic becomes less effective for treatment due to the microbes' ability to adapt through mutations that are resistant to the drug that is left in the body in small quantities.
- Only use antibiotics when necessary.
- Complete the entire cycle of prescribed use of the antibiotic to maximize its effectiveness and not allow for resistance to occur.
- Implement good hygiene to prevent the acquisition of the pathogen in the first place and also use appropriate infection control procedures.
More information regarding the nature of Pathogenic resistance can be referenced here
Example of Drug Resistance: "Super bugs"
"The spread of super bugs: What can be done about the rising risk of antibiotic resistance?"
Mycobacterium tuberculosis (TB)
TB is an infectious disease which is becoming increasingly more resistant to antibiotics. Unfortunately, due to the "overuse and misuse of antibiotics", new strains of antibiotic resistant TB are arising. These strains are spreading throughout the world and becoming "one of the world's most pressing health problems." For example, MDR TB (Multi-drug resistant TB) is a type of tuberculosis that is resistant to two of the most powerful anti-TB drugs.
- The ability for the TB bacterium to evolve into new strains suggests that the genetic variation is already present in the population. Thus, it can respond to selection, resulting in new antibiotic strains.
- The genome of TB is constantly evolving, allowing it to be resistant to drugs.
- HIV infection is linked to multi-drug resistant tuberculosis.
- This article talks about how tuberculosis genomes have led to the pathogen's success.
- TB seems to "place bets on human behavior": always becomes prevalent in high-density populations such as prisons and refugee camps
- bacterium population exploded in 17th century with European colonization around the world (colonial migration & urbanization) ---> current TB pandemic has origins in events of past 3 centuries
- study done by Pepperell showed "highly constrained" TB genome (most mutations discarded quickly), for genes that cause disease in human host
- however, the bacterium's defense genes showed high capacity for mutations that lead to drug resistance ---> keeps TB alive and kicking
- In a recent study, scientists identified that there are 39 genes that make the drug resistance TB different as well as deadly.
- They also found that the disease has been a pathogen to humans and our ancestors for more than 70,000 years.
- Pseudonomas aeruginosa is a common pathogen found in hospitals.
- It is known to affect patients with cystic fibrosis, cancer, AIDS, and patients in the ICU.
- Has developed multi-drug resistance (MDR) to cephalosporins, penicillins, etc. because of genetic events
- Hard to treat in general with antibiotics because of its biofilm formation and ability to communicate via quorum sensing. When antibiotics begin to attack the biofilm, the protected inner layer will begin to increase production and reestablish a strong layer.
- Light microscope image can be found here.
- Read more here.
- This is a journal entry describing the background to Pseudonomas aeruginosa and describes in detail the evolution of it's drug resistance over years. Found here.
MRSA (Methicillin-resistant Staphylococcus aureus)
- Is a more problematic successor of MRSA emerging?
- Here is a link that discusses the evolution of bacteria and specifically details MRSA. Interesting: "Biologists have observed the MRSA strain infecting a single patient evolving through random mutation and selection. The patient was being treated with vancomycin, and slowly, over the course of a few months and 35 separate mutations, the bacteria evolved into a vancomycin-resistant MRSA strain."
- New studies have traced MRSA back to cattle, but the antibiotic resistance evolved after being passed to humans.
- Here is a link about new research that could potentially help reverse antibiotic resistance in superbugs such as MRSA.
- Of the 90,000 Americans who become infected with the drug-resistant MRSA strain each year, 20,000 will die. This is a higher death rate in America than AIDS. (The MRSA Medical Research Center, University of Chicago) Reference
- Some people develop MRSA infections that are treatable while others infected with the same strain develop infections that are significantly more severe and often fatal. It is unknown why this occurs.
- The Tampa Bay Buccaneers, a rival NFL team of the Atlanta Falcons, currrently have an epidemic of MRSA on their football team. Two of their players have contracted the infection, and their entire locker room was sterilized twice in response. This USA Today article chronicles the current event.
- Here is an article and video about how scientist are growing bacteria to find an antibiotic.
- The evolution of the MRSA strain in modern times has created much strife and anxiety in our world. The threat imposed from the bacterial strain prove to be worthy of the fear is is often associated with. Biologists worldwide have attempted to better understand this resistance and fight it. A prevalent issue is the MRSA in relation to bacterial pneumonia. This research article provides information on the topic.
- The flu's ability to evolve so rapidly results in new strains with a variant of the surface protein, hemagglutinin, resulting in ineffective current vaccines and production of new vaccines yearly. Here is an article explaining why this mutation rate prevents a cure for the common cold.
- This article explains the origin and evolution of the flu virus.
- The flu virus has many strains due to mutations and also viral reassortment where two viruses infect one host cell and their genes get mixed around in the nucleus, producing a dangerous, new strain.
- CDC--How the flu virus can change
- Flu trends in the U.S
- One mode of evolution for pathogens is a process called zoonosis in which a pathogen adapts and is able to affect another host species, namely switching from animals to humans. The flu viruses known as Avian Flu and Swine Flu both went through this process and reached near epidemic statuses both in the US and around the world. This article shares more in-depth information on the topic.
- New pandemics in humans occur when new forms of the HA virus jump from animal hosts to humans. (Does this belong with the link above? If so, maybe we can indent it to make that more clear.)
China Bird Flu
- Currently, H7N9 is emerging in China.
- Most concerning aspect of the epidemic is the potential of mutation that Influenza viruses carry.
- The H7N9 virus has a high probability of mutation that could trigger a global pandemic that current vaccinations may not protect against.
- The people primarily affected are those that have been in contact with live poultry markets.
- The disease has taken the lives of 44 people. This relatively low number is attributed to authorities closing many live poultry markets.
- Though the disease is controlled and fading out, it has invoked a fear that other avian influenza viruses may become a prominent issue, given the diversity of the viruses.
- "H7 viruses probably transferred from ducks to chickens on at least two independent occasions and that a so-called 'reassortment' of these viruses with others called H9N2 eventually generated the H7N9 outbreak virus."
- H7N9 was unknown to humans until the outbreak in February and has affected over 140 people throughout China and Taiwan.
- They also found another virus H7N7 that can infect ferrets and can evolve to infect humans.
- Read more here and here! (Maybe make these references more distinct?)
- Here's another link that was interesting about the China Bird Flu, READ MORE
- Recently, the origin and evolution of the virus were discovered and published in a paper in Nature
- This article from the Augusta Chronicle shows how researchers in Georgia (both at Emory and at UGA) are studying the adaptability of the H7N9 virus. These labs are adding characteristics that would make the disease more lethal in order to see how the disease can adapt and could genetically reassort itself with other diseases to create a new pandemic.
- The research they are doing seems risky, but they explain the reasoning as a public health concern that needs to be addressed. It's impressive and enticing to see how understanding the evolution of these diseases will be improve medicine.
- Extra information and a picture of the H7N9 strain can be found at this link.
- Campylobacteriosis is an infection of the gastrointestinal system most commonly occurring as a food borne illness.
- C. jejuni can cause persistent abdominal cramping, diarrhea, and general malaise.
- Historically, the quinolone antibiotic ciprofloxacin (commercially known as Cipro) had been standard treatment for campylobacteriosis.
- In recent years, quinolone antibiotics have become increasingly ineffective in treatment against Campylobacter, due to emerging resistance in some strains of the bacteria.
- More information can be found on CDC's web page on Campylobacter and their 2007 study on fluoroquinolone resistance.
- Analysis experiment of Campylobacter jejuni explaining evolutionary patterns showing patterns may be more systematic then thought. (including graphs and pictures) here.
GonorrheaGram stain of Neisseria gonorrhoeae, a gram negative cocci bacteria stained red here. Original image
- Check out this article that shows the history of antibiotic resistant gonorrhea.
- The United Kingdom's Health Promotions agency reported in 2012 that resistance to antibiotics has actually dropped in gonorrhea during the year 2011 possibly due to the varied use of antibiotics, preventing selection to favor any one type of resistance.
- An article about antibiotic-resistant Gonorrhea cases can be read here.
- The CDC has established the Gonorrhea Isolate Surveillance Program (GISP) to track the progression of drug resistance in global gonorrhea cases.
- Another article of the relevance of evolution in the antibiotic-resistant that was controlled by penicillin and ampicillin in the 1960's. seen here.
- This goes into detail of how North America is beginning to see the evolution of the antibiotic-resistant strain of Gonorrhea that Southeast China already has in 98% of its current strains.
- "Super Gonorrhea" - New strains have an "astonishing ability to mutate rapidly" resulting in new resistance strains. Previously successful antibiotics are now becoming not as effective because of these mutations.
- Trypanosoma brucei is a parasitic protist that causes the disease African Sleeping Sickness. T. brucei is transmitted to humans and animals through infected tsetse flies. There is no vaccine for African Sleeping Sickness because T. brucei changes the expression of its variant surface glycoproteins to escape the host's immune system.
- T. brucei transmitted through the tsetse fly could be an early example of zoonosis.
Antigenic Variation in HIV
Reverse Transcription and the Evolution of HIV
When HIV infects a T cell, reverse transcriptase copies the viral RNA into cDNA. Once the double stranded cDNA segment has been synthesized, it is moved into the nucleus and inserted into the host cell's genome. Reverse transcriptase is a low fidelity polymerase, meaning it has a very high error rate. This leads to a large number of mutations with every replication and further to rapid evolution. Many of the mutations may result in cDNA that is no longer able to code for viral subunits, but some will invariably affect the ability of drugs or the immune system to detect and clear the viral load. This usually occurs through antigenic variation as surface proteins are changed through mutations in the viral cDNA.HIVHIV-1 and AZT Resistance
AZT inhibits the activity of reverse transcriptase and has been used as a primary treatment for HIV infection for many years and was at one point the only available treatment for HIV infection. However, scientists have always known that HIV can develop a resistance to the activity of AZT through various mutations. HIV-1 is a subtype of HIV that has developed this resistance through the development of a pathway that recruits ATP in order to transport AZT out of the cell.
This is a good video illustrating how HIV has developed resistance to first generation antiretroviral drugs and the current drug cocktails that are prescribed to treat HIV infection.
HIV CCR5- Delta 32 Gene
- HIV uses two cell-surface proteins that act as receptors for binding: CD4 and CCR5. CCR5 acts as a co-receptor for CD4; therefore most cells can't be infected by HIV if there is no CCR5 on the surface.
- Many people that are resistant to HIV have a mutation in their CCR5 gene and this mutation is called the CCR5-delta32 gene
- 1% of Caucasians are virtually immune to HIV because they have inherited two copies of the CCR5 gene mutation (CCR5-delta32 gene) from both of their parents.
- Having one copy of the gene mutation for CCR5 is more common and protects you from HIV as in the case of 20% of Caucasians.
- However, even possessing two copies of the CCR5-delta32 gene does not always insure total resistance to HIV because the virus can evolve over time, once in the body, to use a different co-receptor called CXCR4; but, this is very unlikely to occur if the virus is unable to enter cells through CCR5 in the first place
So, where did CRC5-Delta 32 come from?
(citation for picture?)
Some theories suggest that the Delta 32 mutation arose as a form of resistance during the Bubonic Plague, which actively ran through Europe 1347-1351. Scientists analyzed DNA samples from skeletons from the Bronze Age (~3000-1200 BC) and found the same frequency of the of CRC5-Delta 32 as modern populations. A second theory suggested that this gene may have helped mediate Smallpox entry into the cell. However, evidence was not able to support the theory because the first records of small pox are from Asia, and Asians do not carry the CRC5-Delta 32 gene. Secondly, there were no records of Smallpox in Europe until much after the Bronze Age, meaning that the mutation would not have been in response to the Smallpox epidemic. Therefore, CRC5-Delta 32 is not associated with Medieval plagues.
Interestingly, CRC5-Delta 32 does protect again the West Nile Virus, which could lend some clues to the origin of this fascinating gene.
(Source: Uhl, Elizabeth. "Outbreaks and Epidemics." University of Georgia, Athens. October 10, 2013. Lecture.)
Darwinian medicine is the application of the principles of evolutionary biology to the cure of disease and study of disease pathology.
This article, http://www.newscientist.com/article/mg21428600.300-hold-the-painkillers-says-darwinian-paediatrician.html#.Ujx9_GTwK68 on Newscientist shows the opinion of a doctor who claims he is a "Darwinian pediatrician". He believes in methods where instead of immediately trying to reduce swelling by applying ice, individuals should let inflammation happen because it is a natural response that we have evolved to cure ourselves. He also discusses how patients should not take fever reducers and instead allow a fever to run its course. Also, he recommends that parents refrain from giving their infants vitamin K, as he believes that this adaption of low vitamin K levels may have hidden advantages. This belief in the methods of curing and how they change beg the question of whether society really is "short-sighted" and want to heal now as opposed to providing a better immune response over time.
This article http://www.icr.org/article/4349/
argues against the principles of Darwinian medicine by breaking it down to individual components and refuting each part of it.
Good article discussing the possibility that morning sickness is actually the result of evolution:
"The onset of nausea coincides closely with the period of rapid tissue differentiation of the fetus, when development is most vulnerable to interference by toxins. Nauseated women tend to restrict their intake of strong-tasting, potentially harmful substances. This has led researchers to speculate that the nausea of morning sickness is an evolved adaptation which protects the fetus from exposure to toxin"
New techniques are being developed to turn your own body into a self-sufficient Cancer cell killing machine with the use of specialized T-cells, by altering the genome of the cells and re-inserting them into the body of the patient.
An Immune System Trained to Kill Cancer
An interesting article on the rapid developments of antibiotic resistant bacteria. The CDC reports that the overuse of antibiotics (including the potential exposure through the food industry) is leading to a rapid increase in antibiotic resistant bacteria. This poses the problem that there may not be a quick enough development of drugs to respond to the evolution of the bacteria. There is hope through technology by trying to the develop the antibiotics in advance by learning more about the interactions of antimicrobials with the resistant bacteria. The article towards the end does take a weird twist, but the factual evidence is fascinating since it is a bit of a look in how we are currently battling this issue of antibiotic resistant bacteria.