Predicting the duration for development of antibiotic resistance against an antibiotic by an isolated colony of bacteria, using computer simulated “natural” selection
Sidharth.R, KMC Manipal
Introduction
The development of antibiotic resistant strains are on the rise especially in developing countries and are creating a crisis in the effective treatment of infections.1,5
Without horizontal gene transfer, antibiotic resistance develops in most bacteria by mutation in the gene that codes for the enzyme that targets the antibiotic. (B-lactamases in case of B-lactams.)2
The incidence of new forms of isozymes of B-lactamase is rapidly increasing with the increased use of antibiotics like carbapeneme. [blaNDM-1 gene]
The polypeptide sequence of
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The one with the most resemblance is the one with the most chance of occurring naturally.
Calculating the duration to develop resistance
(In this study we assume antibiotics aren’t 100% effective and hence don’t kill all bacteria that don’t contain the “novel” enzyme)
By knowing the DNA sequence of the of possibly antibiotic resistant bacteria, we can determine the minimum number of changes in the base pair sequence required to acquire antibiotic resistance (i.e. comparing the actual DNA sequence with the virtually generated sequence with most resemblance)
Let this number of base pair changes required be = n
Let the avg. number of base pairs mutated per generation (mutation rate) be = m
Let the generation time of the bacterial species be = G
Therefore, the time taken to develop antibiotic resistance in an isolated colony of bacteria (without horizontal gene transfer) =
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Chawla K, Gurung B, Mukhopadhyay C, Bairy I. Reporting Emerging Resistance of Streptococcus pneumoniae from India. Journal of Global Infectious Diseases. 2010;2(1):10-14. doi:10.4103/0974-777X.59245.
2. Bush K, Jacoby GA, Medeiros AA (June 1995). "A functional classification scheme for beta-lactamases and its correlation with molecular structure". Antimicrob. Agents Chemother. 39 (6): 1211–33. doi:10.1128/AAC.39.6.1211. PMC 162717.PMID 7574506.
3. Neu HC (June 1969). "Effect of beta-lactamase location in Escherichia coli on penicillin synergy". Appl Microbiol 17 (6): 783–6. PMC 377810. PMID
found that both the drug and the bacteria use enzymes as their defense and attack
“The Last Resort,” by Maryn McKenna is an article about antibiotic resistance. It explains the increase of carbapenem-resistant Enterobacteriaceae also known as CREs which are a class of antibiotic-resistant bacteria. CREs have been described as “a risk as serious as terrorism”(McKenna, 2013, p.394). CREs can cause bladder, lung, and blood infections that can develop into life-threatening septic shock. Unfortunately, it kills half of the people who contract it. This bacteria is resistant even to carbapenems, which are considered drugs of last resort because of the serious health risks in taking them. “Antibiotics have been falling to resistance for almost as long as people have been using them; Alexander Fleming, who discovered penicillin, warned about the possibility when he accepted his Nobel prize in 1945”(McKenna, 2013, p.394). Although CREs was first discovered almost 15 years ago, it did not become a public-health priority until just recently. The North Carolinan strain of Klebsiella produced an enzyme called Klebsiella pneumoniae carbapenemase or KPC for short. It broke down carbapenems which made the strongest antibiotic now resistant. “Physicians find themselves caught between using bad drugs or using no drugs at all”(McKenna, 2013,
Drug resistance is more likely to develop in a species of bacteria that can double its population every 20 minutes because of the amount of bacteria that that is created in a
For a bacterium to become resistant a change in its DNA must occur. This can happen in more than one way. Bacterium may gain resistance through spontaneous mutation within the bacterium’s DNA. This occurs when a single amino acid that makes up a protein changes arrangement, the order of the peptide chain (made up of amino acids, joined together to make up proteins) then the purpose of the protein in the DNA changes. This causes the genetic makeup of the cell to alter. If the mutation is of benefit and gives the bacteria resistance, once all the other none resistant strains of bacteria are killed, the resistant bacteria multiplies and reproduces, creating a new strain of bacteria which is resistant to the antibiotic in hand. Once a resistance gene is obtained and inserted into the DNA, the bacterium can dominate other bacteria and
Since the 1940s there has been an increase of antimicrobial resistance towards antimicrobial drugs, because the use of antibiotics has increased and microbes are
Antibiotic resistance is and continues to be a global public health issue1.One of the main concerns stems from the ability for bacteria to obtain antibiotic resistance very easily as a result of chromosomal changes, or through plasmids and transposons which generate an exchange of genetic material2. Resistance can also result from single or multiple mutations1,3. To combat this rising force, scientists must research and analyse the many possibilities of mutations in a variety of genes and proteins in specific bacteria and ways to combat them.
Intrinsic resistance is achieved by spontaneous gene mutation through replication where acquired resistance results as an adaptation technique when bacteria in contact with antibiotic. Pathogenic bacteria can gain resistance through several mechanisms such as acquire modification of active site of the bacteria in turn results in reduction in the efficacy of binding of the drug, direct modification or destruction of antibiotic by enzymes produced by bacteria or efflux of antibiotic from the bacterial cell through efflux pumps. Bacterial species accomplish spreading the resistance through horizontal gene transfer mechanisms such as transformation, transduction and conjugation via plasmids.
The development of antibiotics was an important advancement in 20th century medicine. Previously deadly infectious diseases are now routinely treated with antibiotics. Moreover, for modern-day medical procedures such as chemotherapy treatment to be successful, antibiotic use is necessary. For these reasons, the prospect of bacteria developing widespread resistance to antibiotics is a major concern as it would render many modern-day medical therapies unviable.
Bacterial Pathogens have been developing resistance to antibiotic treatment soon after these drugs were developed. Mutations in the genes of the bacteria allow it to survive despite being exposed to the medications designed to kill them. Through directional selection, the bell curve is shifted to a phenotype that is designed to survive in harsh conditions that would normally kill them.
Discussion: If a bacterial strain is susceptible to an antibiotic, it can be inhibited by a concentration of this drug. The antibiotic will be associated with a high chance of therapeutic success. If a bacterial strain is said to be intermediate when it is inhibited by a concentration of this drug, then it is associated with an uncertain therapeutic effect. And if a bacterial strain is said to be resistant to an antibiotic, then this drug is associated with a high chance of therapeutic failure.
Less than 50 years after penicillin was discovered, strains of bacteria were discovered to be resistant to antibiotics (Haddox, 2013). Over the years scientists have changed the structure of the antibiotics to avoid this resistance, every time the bacteria adapts to overcome the changes. Bacteria divides as fast as 20 minutes and have many different ways to adapt (Haddox, 2013). Bacteria pass their drug resistance between strains and species, causing antibiotics to be less effective to all bacteria (Haddox, 2013).
The phenomenon of antibiotic resistance occurs when bacterial organisms can resist – via several different avenues – the harmful effects of antibiotic drugs, which ultimately results in a selective advantage that is not shared amongst the remainder of the population that is still susceptible to the effects of the drugs. There are numerous ways that bacteria are known to show resistance to antibiotics. Some bacteria can modify the chemical nature of the drug, making it ineffective, and yet some possess a different form of target site that the drug is not compatible with, which inhibits the drug’s ability to bind to the bacterial cell. When coupled with prevalent antibiotic use amongst human populations, these acquired mechanisms of resistance can be selectively advantageous to the bacteria in possession of them. Being resistant to one or more antibiotic drugs means that these bacteria can survive and pass on their genes for resistance to their offspring, which can have negative effects on human populations, especially in the healthcare setting. Antibiotic resistance has garnered much attention in recent years across the developed world, as pathogenic microbes become resistant to more and more antibiotics thanks to both the overuse and misuse of these drugs. The increased frequency of which this problem has
Antibiotic resistance is a growing problem that must be addressed on a clinical, economical, and research level. According to the antimicrobial resistance AMR, by 2050 “10 million more people would be expected to die every year than would be the case if resistance was kept to today’s level”. Due to over exposure do antibiotics bacterial pathogens have developed both defenses and offenses against antibiotics. These mechanisms provide bacteria to survive antibiotic level that human bodies cannot tolerate. In order to combat this problem two main avenues exist. The first option is big pharmaceutical companies and startup biotechnology companies, backed by venture capitalism, can develop new antibiotics. This process however is not profitable
Antibiotic resistance occurs when antibiotics are no longer effective in controlling bacterial growth. The phenomenon of antibiotic resistance can be explained by the processes of selective pressure in which the strongest strains of bacteria survive antibiotic therapy, resulting in "superbugs" that are resistant to almost every type of antibiotic available for use (Davies & Davies, 2010). Because of this, certain bacterial infections are evolving that have no effective treatments. This resistance creates a threat to the common medicinal practices of today and can be seen as a global problem; perhaps one of the world's most serious problems. The issue of antibiotic resistance is emerging rapidly as a result of a myriad of uniformed practices and misuse of antibiotics.
This optimism has been dissipated long before the 20th century when the proliferation of antibiotic resistance bacteria became evident as Fleming predicted earlier. With the rapid development of infectious disease associated with antibiotic resistance forced us to change the way we view disease and the way we treat patients.