While an antibiotic drug refers specifically to one intended to halt or eliminate a specific species of bacterium or range of bacteria, an antimicrobial drug may be intended to treat any of several classes of microorganism, including parasites, viruses, and fungi.
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Antibacterial or antimicrobial resistance, therefore, refers to the evolution of mechanisms within an organism (bacteria or another microorganism, respectively) that lessen the efficacy of such drugs, potentially reaching a point where they become entirely ineffective.
Microorganisms can adapt to survive through a process of evolution that enhances the propagation of successful genes in the population, and in the case of pathogenic organisms, human-applied therapies present a particularly strong encouraging factor. Since the first widespread use of antibiotics resistance to drugs has been increasingly reported amongst bacterial strains, with some eventually adopting multiple methods of resistance that make them immune to almost any conventional therapy, known as multi-drug resistant bacteria.
The number of novel ways that bacteria have evolved to evade or suppress the influence of a drug is plentiful, common examples include the development or improvement of efflux pumps, alteration of drug entry methods, the evolution of drug disabling enzymes, and many others. Similarly, other microorganisms may go about developing resistance concerning the particular nuances and mechanism of action of the drug in question, limited only by the physical characteristics of the organism.
For example, as a virus bears no membrane proteins the evolution of resistance by increased efflux pump activity can not be achieved, but the drug may be prevented from interacting with its prior target site by alteration of the structure of an essential protein.
Drug resistance in protozoa
Malaria is caused by microorganisms belonging to the Plasmodium group, unicellular eukaryotes, that require residence in insect and vertebrate animals as a part of their life cycle and are thus known as obligate parasites. Five known malaria species affect humans, each needing to be transferred to a human by Anopheles mosquito, whereupon the parasite replicates asexually.
Following replication a subsequent bite by another Anopheles mosquito allows cells that have differentiated into gametocytes to spread to the insect, propagating the process. Several anti-malaria medications have been developed, some being specific to the target species of Plasmodium parasite, while others are intended as broad-spectrum antimalarials, with quinine-based drugs being popularly employed for several decades.
Chloroquine and other similar drugs act against the parasite by inhibiting the formation of hemozoin, a product of sequestered host hemoglobin that is used as an energy source. Several genes have been associated with resistance to these drugs, with, for example, PfCRT (P. falciparum chloroquine resistance transporter) coding for a protein that is responsible for enhanced efflux of the drug from the parasite digestive vacuole.
A specific mutation (K76T) is the primary reason for the development of this resistance mechanism, wherein a positively charged lysine residue is exchanged for a neutral threonine residue, allowing chloroquine to interact with active transporter proteins.
Other mutations have since developed that support this mechanism of resistance, though only in association with this original mutation. This and other mutations have now become dominant amongst some strains of the parasite, particularly in southeastern Asia, and chloroquine resistance has contributed to a global increase in malaria-related deaths.
Is antibiotic resistance more widespread?
What causes antibiotic resistance? - Kevin Wu
Given the relatively greater occurrence of pathogenic bacterial infections that require medical intervention in comparison to those caused by parasites or fungi, antibiotics are generally far more widely distributed and administered, particularly in a prophylactic capacity both in humans and in agriculture, and are therefore more likely to be given unnecessarily, promoting drug resistance.
The discovery and implementation of each of the major classes of antibiotics have taken place relatively quickly, with the earliest mass-produced forms emerging in the early 20th century and the latest towards the end, with no significant advances having been made since. In comparison, the development of antiviral drugs has been minimal, largely due to the difficulties involved in setting up a representative in vitro and in vivo study that depends on access to a suitable host.
Given the much earlier and wider distribution of antibiotics, it is unsurprising that extreme resistance has been observed to develop more readily in bacteria than other microorganisms, though other factors such as replication time and method, degree of communal cooperation, and plasticity of the genome also play a large role in determining the likelihood of resistance developing in any particular microorganism.
The development and persistence of resistance mechanisms in a population have also in some cases been associated with the process of horizontal gene transfer, wherein the genetic information regarding a newly evolved advantage is passed to another organism other than by the ordinary “vertical” route from the parent to offspring.
Bacteria are well known to utilize several horizontal gene transfer techniques that contribute significantly to drug resistance in a population, and though less well understood in other microorganisms such as fungi, parasites, and viruses, they also engage in horizontal gene transfer between individuals and with the host, allowing them to spread beneficial mutations or better adopt host cellular machinery, though potentially to a lesser extent than seen in bacteria.
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Further Reading
Trends in antibiotic usage among inpatients in South America during COVID-19 pandemic