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The early discovery and development of antimicrobial drugs and agents have revolutionised medicine in many aspects, saving countless lives since their discovery over 70 years ago. This was a turning point in human history as they have been used to treat infectious diseases and have significantly reduced illnesses and deaths occurring as a result. Treatments for infections initially began roughly 2000 years ago by ancient Egyptians, Greeks and the Chinese whereby extracts from both mould and plants were used to treat infections. Additional discoveries were then made by several scientists including Louis Pasteur, Edward Jenner and Alexander Fleming. Nobel Prize winner Fleming discovered Penicillin on culture dishes that were being used to study Staphylococcus. Fleming noticed that mould had developed on the agar, which had created a zone of inhibition around the colony. He experimented further and later named the Penicillin after the fungus Penicillium chrysogenum. His work was further developed after his death by Ernst Chain and Howard Florey. By 1940 penicillin was being mass produced as a drug and has since been used to treat individuals suffering from infectious diseases.
Antimicrobial resistance (AMR) refers to an infectious micro-organism that is able to resist and survive exposures of a relevant concentration of an antimicrobial drug, which would otherwise destroy sensitive organisms of the same strain. Antibiotic resistance maybe due to a number of acquired factors, such as:
Development of an alternative metabolic pathway that is able to bypass a specific reaction that would normally be inhibited by the drug.
A drug altering the production of an enzyme.
The synthesis of excess enzyme over the amount that can be inactivated by the antimicrobial drug.
The inability of the drug to penetrate into the cell due to a specific alteration of the cell membrane.
The alteration of ribosomal structure.
Microbes that have developed a tolerance for a new environmental condition have been shown to resist the effects of one antimicrobial drug. Therefore, they have only developed a single strain that can endure the effectiveness of a particular drug. This is then able to survive and reproduce within the new conditions. This microbe will only become a multidrug resistant bacterium once it progresses to resist multiple drugs allowing it to mutate, giving it the capability to survive the tolerance of the new antimicrobial drug it may be exposed to. Examples of this are Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa.
Bacteria are able to gain resistance in various ways. However, there are two distinct processes that of how this can occur:
Spontaneous mutation: This is a rare spontaneous change to random characteristics within the genes of a bacterial population. These mutations involve the replacement of a particular nucleotide, frame-shift, deletion, inversion, or insertion. The mutating rate may differ depending on a mutagenic influences, such as:
Ultra Violet radiation
Horizontal Gene Transfer (HGT) (infectious transfer): This is defined as the transfer of generations of genetic material between organisms without reproduction. It is a process occurring during cell division and is part of bacterial evolution involving bacteria to adapt and adjust to new environments. This may result in the acquisition of new or altered genes via modification of gene functions. SCC (Staphylococcal Cassette chromosome mec) is known to carry two specific chromosome recombinases (recombinase A and B). Both play a significant role as they carry the mec gene complex, which encode for the beta lactams and resulting in the resistance of Staphylococcus aureus to methicillin. As bacteria are unable to reproduce sexually they have evolved to reproduce using numerous mechanisms in order to exchange genetic material. These are known as:
There are other occurrences that have shown a connection with the development of bacterial resistance, which are:
Gene pick up
Chromosomal aberration and subsequent replication
FIGURE ONE: The three mechanisms of HGT: Transformation: The alteration of short, naked DNA fragments within a bacterial plasmid. Conjugation: The transfer of genetic material primarily mediated by conjugal plasmids or conjugal transposons. This involves temporary cell to cell contact between two bacteria and the transfer of long DNA fragments. Transduction: The transfer of DNA to close related bacteria via a plasmid or bacteriophage.
A problem that has progressively evolved during recent years is the issue dealing with the microbes that have developed a tolerance and have become resistant to multiple antimicrobial drugs. These are more commonly known as multidrug resistant MDR) bacteria or a superbug. An example of an MDR is Extended Spectrum Beta Lactamase (ESBLs) producing bacteria. Due to its advancement in becoming resistant to numerous drugs, ESBLs and other multidrug resistant bacteria are becoming a problem globally due to its evolved resistance genes and are being accountable for causing an increase in mortality and morbidity internationally. This is becoming an issue globally as the standard treatments that are typically used to destroy these microbes within the body are becoming ineffective to the microorganism and consequently resulting in infections spreading to others with the mutated strain developing one or more resistance genes.
Previous evidence has shown that antibiotic resistance may be caused by a natural occurrence due to a process known as the Environmental Resistome. The genes involved in this process can be transferred from a harmless non-disease causing microbe to a microbe that is able to spontaneously cause diseases. This can potentially lead to a clinically significant antibiotic resistance.
Methicillin-resistant Staphylococcus aureus (MRSA)
Methicillin resistant Staphylococcus aureus (MRSA) is a bacterium known as Staphylococcus aureus. It is a strain that has become resistant to the antibiotic methicillin and is becoming increasingly difficult to treat in patients as it is becoming multi drug resistant. MRSA is a global problem particularly in hospitals as patients with open wounds are more susceptible to acquiring the infectious disease as a result of their weakened immune system.
It has been discovered that MRSA has 16 different strains, with 2 of them (strains ST22/EMRSA-15 and ST30/EMRSA-16) having an increased risk of transmission. In 1959, a new antimicrobial drug known as methacilin was used to treat individuals who were infected with penicillin-resistant Staphylococcus aureus, which is semisynthetic. However, shortly after in 1961 when Staphylococcus aureus had shown isolates that had gained resistance to the methicillin antibiotic, which gave rise to methicillin-resistant Staphylococcus aureus (MRSA). Some strains were incapable of resisting the antibiotics and were therefore known as methicillin-sensitive Staphylococcus aureus (MSSA). Other new penicillin's that emerged after, such as dicloxacillin, nafcillin, oxacillin also acquired resistant strains after a short period of time. These resistant isolates were also recovered globally and became a problem within the community (CA-MRSA) and hospitals (HA-MRSA).
It has been defined that MSRA first arose when it developed a large chromosome known as the Staphylococcal Cassette chromosome mec (SCCmec). The deletion of ccr (cassette chromosome recombinase) has been known to be the reason behind the emergence of SCCmec in various MRSA isolates.The resistance of Staphylococcus aureus to methicillin is facilitated by the exogenous gene PBP2a (Penicillin -binding protein 2a), which is a binding protein. PBP2a is present on the membrane of MRSA and has a low affinity to beta lactams, which is encoded by the gene mecA. This then prevents the antimicrobial drug such as penicillin and methicillin from cell wall destruction. The inheritance pattern of the mecA gene is poorly understood. However, it is known that it may have genetically evolved via the ancestral Staphylococcus aureus strain.
Glycopeptide antibiotics such as vancomycin and teicoplanin are currently the only effective antibiotics of treating MRSA. These were introduced in 1991 to combat MRSA. However, research shows that MRSA has shown susceptibility to them as well. These have been named vancomycin-intermediate Staphylococcus aureus (VISA) and vancomycin-resistant Staphylococcus aureus (VRSA). The resistance of vancomycin occurs by a mutation of the cell wall, preventing the incorporation of N-acetylemuramic acid. Resulting to it becoming thicker due to the accumulation of peptidoglycan. The excess in peptidoglycan results in the vancomycin getting captured and not allowing it to get in contact with the cytoplasmic membrane. In 1996 two vancomycin resistant strains (Mu3 and Mu50) were isolated from patients. Various classes of vancomycin known as hetero-VRSA and VRSA are produced within the population.
Pseudomonas aeruginosa is recognized by its high intrinsic resistance to antimicrobial drugs. It is known to be a major cause of nosocomial infections globally and is difficult to control and treat within an infected individual. This is due to its capability to acquire a natural resistance. The bacterium has the ability to survive and thrive especially within immunocompromised individuals, which enables to cause various infections and health problems.
The bacterium is known to have significant resistance against several groups of drugs due to factors such as:
Its ability mutate and resist the effects of all appropriate treatment. This leads to chromosomal genes to then regulate resistance genes.
Having the ability to cause implications within an individual suffering from a severe infection.
Enabling it to become intrinsically resistant to antimicrobial agents due to low permeability of its cell wall.
Having the genetic ability to express a wide range of resistance mechanisms
Acquiring supplementary resistance genes from other organisms via plasmids, transposons and bacteriophages.
REF: b Mechanisms of antibiotic resistance in Pseudomonas aeruginosa P A Lambert
Pseudomonas aeruginosa is known to have 5570 genes and an abundant number of regulatory genes, aiding this bacterium to evolve and mutate rapidly against antibiotics. The importance of the outer membrane is crucial to the understanding of how it gains resistance. The outer membrane consists of a lipopolysaccharide phospholipid bilayer containing protein channels known as prions. These are fundamental for the diffusion of molecules through the cell. The resistance is known to be the reasoning of various factors involving the low permeability of the outer membrane. Thus restricting uptake via the outer membrane allowing factors such as cationic antimicrobial peptides to produce porins (known as OprF) through the membrane. The absence of OprF has been found to be a main factor of the bacterium's resistance to antibiotics. This leads to cells in the membrane becoming more vulnerable to antibiotics. Also, secondary resistance within the AmpC beta-lactamase and changes through mutation have proven to make cells resistant to a range of antibiotics.
The ability for this bacterium to be resistant to multiple drugs can also be caused by mutations in genes mexAB, mexXY which then overexpress separate efflux systems known as:
These are then responsible for causing mutations to multiple antibiotics and lead to the over expression of related factors, which then lead to new isolates acquiring resistance to a specific antibiotic.
Pseudomonas aeruginosa is known to have a low antibiotic susceptibility to drugs, which makes it difficult to treat infected patients. The antibiotics that show affect the bacterium such as aminoglycosides and quinolones must be given via an injection in order for some establishments to minimise the amount of resistant strains of Pseudomonas aeruginosa.
The rapid emergence of bacterial strains characterised to resist multiple therapeutic drugs is a growing global challenge, impacting all mainstream pharmaceutical antibiotics. The exploitation of drugs has also played a role in the emergence of microorganisms becoming resistant with this spreading internationally. Individuals using antimicrobial drugs irrationally by not taking the full course prescribed or when poor antimicrobials have been used to treat an individual aids bacteria to become resistant. The mechanisms responsible for the evolution of bacteria are not clearly understood, yet they could play a vital role in the resistance of bacteria to specific antimicrobial drugs and agents. This aspect is essential as the diverse environments that microbes encounter within the human body can alter the microbe depending on the drug concentrations it is exposed to.
Controlling infectious diseases is becoming threatened by the increase of microorganisms that are becoming resistant to antimicrobial agents. There are various approaches of how management and treatment of drugs can aid in the prevention of bacterial resistance. This will greatly aid antibiotics that are being used at present. This will delay the evolution of drug resistance, developing mechanisms to evade the antibiotics.
There are several current approaches that can be taken to reduce bacterial resistance to antibiotics within hospitals and communities these are:
Isolating individuals with potentially resistant strain of an infectious disease:
Research has shown that isolating individuals within special units has significantly lowered the chances of transmitting bacteria to other patients. This has proven to be useful within the hospital wards and in surrounding hospitals in the area.
Tracking the frequency of resistance:
In order to keep track of areas that are affected with a resistant bacterial strain, global surveillance and constant communication is needed in order to initiate a global response. This would aid in the existing status of the resistance within that specific area allowing the appropriate medication to be used for treatment. This is advantageous as it will inform the appropriate bodies to new information, such as new emerging strains, leading to the appropriate action to be taken to treat those individuals.
Inducing advanced therapeutic approaches:
Ensuring health care providers prescribe the right antibiotics and reduce any unnecessary antibiotic use. Also, ensuring that the complete course of antibiotics is taken even after feeling better. This is an important factor as the amounts of treatments that are available have reduced significantly. If antimicrobial resistance is reduced, it will allow effective therapy to resurface in the near future.
Ensuring that the antibiotics are not used again in the future. This will allow the bacteria to become resistant quicker if taken again.
Hospital and health care infection control:
Infection control plays a key part in controlling the spread of the infection to other individuals. Hospital and health care staff must be trained on hygiene to prevent the spread of disease. Basic responsibilities such as:
Washing hands with soap and water, as well as using disinfectants such alcohol gels.
Wearing sterile barrier precautions such as gowns, gloves, caps and masks when treating infected individuals.
Providing healthcare workers with available vaccinations for protection against infected individuals. Prophylaxis should be used if a vaccination for a particular bacterium is not yet available.
Preventing establishments such as pharmacies from selling antibiotics easily over the counter. This will only aid the resistance of bacteria as it will assist them in becoming immune to the treatment if taken wrongly.
Future solutions that are being researched to combat antimicrobial resistance include:
This is the therapeutic utilisation of bacteriophages to treat infectious bacterial agents. This method involves bacteriophages to invade bacterial cells and inject their viral genome in the cell until it lyses. This interrupts the normal functions of the bacterial cell and is used for treatment. This method has several potential advantages such as:
Being more effective than antibiotics and therefore having better results when a patient is being treated.
Bacterial phage resistance has the potential to occur. However, development of a new phage is easier than to improve than a new antibiotic. This method will only take a number of weeks in comparison to a new drug.
Phage's have the ability to stop reproducing once the target bacteria have been degraded.
There are many advantages to this technique of eventually reducing infectious diseases. There have been positive results from countries, such as Russia who have attempted this method on various bacterial infections. However, this procedure has general obstacles that are still being overcome in order to perfect it for its utilisation in hospitals and other healthcare practises.
The discovery of quorum sensing originated in the bacteria Vibrio fischeri. The idea behind bacterial communication has allowed scientists to research in to how bacteria coordinate gene expression with the consideration of density and the local population within a specific area. It is achieved by disrupting signalling molecules known as autoinducers or pheromones between bacteria. Communication occurs when signalling molecules bind to a specific receptor present on the cell surface. This induces transcription of genes, which are activated by various secreted molecules present in the environment and initiating communication for the bacteria to respond simultaneously.
Quorum sensing can aid in combatting antimicrobial resistance as research into interrupting the signalling molecules from attaching on to the surface receptors will prevent a response occurring. This will allow white blood cells to eliminate pathogens from the host. Quorum sensing has shown promising results when studied on the bacterium's Pseudomonas aeruginosa, Salmonella enterica, Escherichia coli and more. Further advancements in the field of quorum sensing are being undertaken in order to trial it upon other virulent bacteria to allow it to be a potential treatment for the future.
Vaccines have been used for numerous years in order to aid the body's immune system against harmful pathogens that could potentially harm the body. They are able to enhance the immune system using its natural defences to treat infections. This development is able to dramatically decrease the amount of antimicrobial resistant infections and potentially eliminate them. However, a disadvantage includes having to work with new strains that may emerge and evolve. This will result in having to produce new vaccinations to combat the new strains.
Other promising developments such as alternatives to antibiotics, probiotics, trace elements and phytochemicals are all in development in order to reduce or possibly eradicate antimicrobial resistance.
Overall, antibiotics have revolutionised medicine by being able to effectively treat bacterial infections within individuals. However, it has been a challenging issue for several years due to the emergence and evolution of bacterial resistance. This has been approached successfully in the past but the amount of antibiotics that are available to effectively eradicate an infection has significantly reduced.
The developments that are progressing to eliminate or reduce antibiotic resistance are encouraging as they involve working with the organisms to inhibit resistance as appose to killing the bacteria rapidly and allowing the white blood cells to remove them from the body. However, this will only be successful if minor but effective approaches, such as the factors mentioned above, are taken seriously.