Antimicrobial Resistance Mechanisms

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One of the most pressing global health issues is the problem of resistance to antimicrobial drugs. Antimicrobial resistance contributes to the uncontrolled increase in the number of pathogenic microorganisms, which leads to higher levels of infectious diseases.

Antimicrobial resistance complicates the prevention and treatment of diseases, caused by bacteria, viruses, fungi and parasites. More and more countries are beginning to focus on this issue, as it poses a threat not just to countries on the individual level, but to the whole world.

For this reason, the global action plan on antimicrobial resistance was adopted in May, 2015 at the 68 World Health Assembly.

One of the five strategic objectives of the plan is to strengthen the evidence base through global surveillance and researches in the field of antimicrobial resistance. According to statistics, the number of antibacterial drugs in recent years has increased, along with which antimicrobial resistance has also shown a considerable growth.

A number of factors contributes to the growth of drug resistance level. As pointed out by the WHO in 10 facts on antimicrobial resistance, the use of sub-therapeutic doses of antibiotics in animal and poultry feed contributes to antibiotic resistance increase.

The other factors, contributing to antimicrobial resistance also include weak surveillance systems, poor infection control and prevention. Great concern with the issue of drug resistance development served as the basis for the global antimicrobial resistance researches, carried out by the WHO in collaboration with member states.

In 2014, the WHO presented a paper “Antimicrobial resistance: Global report on surveillance in 2014”, which identified the key areas of the fight against antimicrobial resistance. The main attention was paid to the antibacterial resistance in the treatment of such diseases, as malaria, tuberculosis and HIV.

It should be noted that modern medicine distinguishes two types of antimicrobial resistance:

–  acquired

– natural (intrinsic)

The appearance of acquired resistance in a microorganism is not always associated with the reduction in clinical efficacy of antibacterial drugs. Such antimicrobial resistance develops under the influence of various environmental factors. As a result of this influence, the microbe acquires new properties or loses its old qualities.

The drug resistance often develops as a result of the microbial strains evolution and misuse of antimicrobial drugs. The evolution of resistant strains is considered to be a natural phenomenon that occurs in faulty reproduction or mutations of microbes.

Reasons for the development of antimicrobial resistance are diverse, the most important being irrational and misguided use of antibiotic drugs, among which are:

–  wrong drug choice

– unjustified prescription of antibiotics

–  wrong choice of dosage regimen

–  unreasonably long use

Natural (intrinsic) antimicrobial resistance is characterized by the inaccessibility of antimicrobial agent for affecting the target, due to the enzymatic activation or the primary low permeability. It often happens that the microorganism totally lacks the target for the effect of the antimicrobial drugs.

Researches have shown that antibiotics are clinically ineffective in the presence of the natural resistance in microorganisms.

The mechanism of antimicrobial resistance is often based on the modification of the antibiotic action target, antibiotic excretion from microbial cells, formation of metabolic shunt, antibiotic inactivation, violation of permeability in microbial cells outer structure.

It should be noted that various microorganisms are characterized by their mechanisms of resistance development. Researchers recommend using antibiotics with a specific range of action after determining sensitivity to them for reducing antimicrobial resistance in humans.

Patients should strictly comply with the recommended dosage and treatment duration. Rotation of antimicrobial drugs is also recommended to reduce the risk of drug resistance.

Recent researches have shown that the rotation of antimicrobials (e.g. using antibiotics with different mechanisms of action) reduces the incidence of infections.

To prevent antimicrobial resistance, it is necessary to adhere to the following principles:

use antibiotics with a narrow spectrum of action

use the parenteral route of antimicrobials administration

minimize local administration of antimicrobials

carry out therapy with the maximum doses until the infection is completely overcome

limit the use of drugs, intended for humans, in the food industry and the veterinary

periodically assess the type of pathogen and resistance of microbial strains for the purpose of effective antimicrobials selection.

Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have emerged not only in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic “attack” is the prime example of bacterial adaptation and the pinnacle of evolution. “Survival of the fittest” is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice providing specific examples in relevant bacterial pathogens.

The discovery, commercialization and routine administration of antimicrobial compounds to treat infections revolutionized modern medicine and changed the therapeutic paradigm. Indeed, antibiotics have become one of the most important medical interventions needed for the development of complex medical approaches such as cutting edge surgical procedures, solid organ transplantation and management of patients with cancer, among others. Unfortunately, the marked increase in antimicrobial resistance among common bacterial pathogens is now threatening this therapeutic accomplishment, jeopardizing the successful outcomes of critically ill patients. In fact, the World Health Organization has named antibiotic resistance as one of the three most important public health threats of the 21st century.

Infections caused by multidrug-resistant (MDR) organisms are associated with increased mortality compared to those caused by susceptible bacteria and they carry an important economic burden, estimated at over 20 billion dollars per year in the US only. The Centers for Disease Control and Prevention conservatively estimates that at least 23,000 people die annually in the USA as a result of an infection with an antibiotic-resistant organism.

Moreover, according to a recent report, antibiotic resistance is estimated to cause around 300 million premature deaths by 2050, with a loss of up to $100 trillion (£64 trillion) to the global economy. This situation is worsened by a paucity of a robust antibiotic pipeline, resulting in the emergence of infections that are almost untreatable and leaving clinicians with no reliable alternatives to treat infected patients.

In order to understand the problem of antimicrobial resistance, it is useful to discuss some relevant concepts. First, antimicrobial resistance is ancient and it is the expected result of the interaction of many organisms with their environment. Most antimicrobial compounds are naturally-produced molecules, and, as such, co-resident bacteria have evolved mechanisms to overcome their action in order to survive. Thus, these organisms are often considered to be “intrinsically” resistant to one or more antimicrobials. However, when discussing the antimicrobial resistance conundrum, bacteria harboring intrinsic determinants of resistance are not the main focus of the problem. Rather, in clinical settings, we are typically referring to the expression of “acquired resistance” in a bacterial population that was originally susceptible to the antimicrobial compound. As it will be discussed later in the chapter, the development of acquired resistance can be the result of mutations in chromosomal genes or due to the acquisition of external genetic determinants of resistance, likely obtained from intrinsically resistant organisms present in the environment.

Second, it is important to recognize that the concept of antimicrobial resistance/susceptibility in clinical practice is a relative phenomenon with many layers of complexity. The establishment of clinical susceptibility breakpoints (susceptible, intermediate and resistant) mainly relies on the in vitro activity of an antibiotic against a sizeable bacterial sample, combined with some pharmacological parameters (e.g., blood and infection site concentrations of the antimicrobial, among others). Thus, when treating antibiotic-resistant bacteria, the interpretation of susceptibility patterns may vary according to the clinical scenario and the availability of treatment options. For instance, the concentration of gentamicin achieved in the urine may be sufficiently high to treat a lower urinary tract infection caused by an organism reported as gentamicin-resistant. Similarly, different penicillin breakpoints have been established for Streptococcus pneumoniae depending if the isolate is causing meningitis vs. other types of infections, taking into account the levels of the drug that actually reach the cerebrospinal fluid. In addition, the in vivo susceptibility of an organism to a particular antibiotic may vary according to the size of the bacterial inoculum, a situation that has been well documented in Staphylococcus aureus infections with some cephalosporins. Indeed, there is evidence to suggest that some cephalosporins (e.g. cefazolin) may fail in the setting of high-inocula deep-seated infections caused by cephalosporin-susceptible S. aureus. Thus, in the following sections, we will focus on the molecular and biochemical mechanisms of bacterial resistance, illustrating specific situations that are often encountered in clinical practice.

 

GENETIC BASIS OF ANTIMICROBIAL RESISTANCE

Bacteria have a remarkable genetic plasticity that allows them to respond to a wide array of environmental threats, including the presence of antibiotic molecules that may jeopardize their existence. As mentioned, bacteria sharing the same ecological niche with antimicrobial-producing organisms have evolved ancient mechanisms to withstand the effect of the harmful antibiotic molecule and, consequently, their intrinsic resistance permits them to thrive in its presence. From an evolutionary perspective, bacteria use two major genetic strategies to adapt to the antibiotic “attack”, i) mutations in gene(s) often associated with the mechanism of action of the compound, and ii) acquisition of foreign DNA coding for resistance determinants through horizontal gene transfer (HGT).

Mutational Resistance

In this scenario, a subset of bacterial cells derived from a susceptible population develop mutations in genes that affect the activity of the drug, resulting in preserved cell survival in the presence of the antimicrobial molecule. Once a resistant mutant emerges, the antibiotic eliminates the susceptible population and the resistant bacteria predominate. In many instances, mutational changes leading to resistance are costly to cell homeostasis (i.e., decreased fitness) and are only maintained if needed in the presence of the antibiotic. In general, mutations resulting in antimicrobial resistance alter the antibiotic action via one of the following mechanisms, i) modifications of the antimicrobial target (decreasing the affinity for the drug, see below), i) a decrease in the drug uptake, ii) activation of efflux mechanisms to extrude the harmful molecule, or iv) global changes in important metabolic pathways via modulation of regulatory networks. Thus, resistance arising due to acquired mutational changes is diverse and varies in complexity. In this chapter, we will give several examples of antimicrobial resistance arising through mutational changes (see below).

Horizontal Gene Transfer

Acquisition of foreign DNA material through HGT is one of the most important drivers of bacterial evolution and it is frequently responsible for the development of antimicrobial resistance. Most antimicrobial agents used in clinical practice are (or derive from) products naturally found in the environment (mostly soil). As mentioned before, bacteria sharing the environment with these molecules harbor intrinsic genetic determinants of resistance and there is robust evidence suggesting that such “environmental resistome” is a prolific source for the acquisition of antibiotic resistance genes in clinically relevant bacteria. Furthermore, this genetic exchange has been implicated in the dissemination of resistance to many frequently used antibiotics.

Classically, bacteria acquire external genetic material through three main strategies, i) transformation (incorporation of naked DNA),  transduction (phage mediated) and, conjugation (bacterial “sex”). Transformation is perhaps the simplest type of HGT, but only a handful of clinically relevant bacterial species are able to “naturally” incorporate naked DNA to develop resistance. Emergence of resistance in the hospital environment often involves conjugation, a very efficient method of gene transfer that involves cell-to-cell contact and is likely to occur at high rates in the gastrointestinal tract of humans under antibiotic treatment. As a general rule, conjugation uses mobile genetic elements (MGEs) as vehicles to share valuable genetic information, although direct transfer from chromosome to chromosome has also been well characterized. The most important MGEs are plasmids and transposons, both of which play a crucial role in the development and dissemination of antimicrobial resistance among clinically relevant organisms.

Finally, one of the most efficient mechanisms for accumulating antimicrobial resistance genes is represented by integrons, which are site-specific recombination systems capable of recruiting open reading frames in the form of mobile gene cassettes. Integrons provide an efficient and rather simple mechanism for the addition of new genes into bacterial chromosomes, along with the necessary machinery to ensure their expression; a robust strategy of genetic interchange and one of the main drivers of bacterial evolution. For details on the mechanisms of HGT the readers are directed to a recent state-of-the-art review.

MECHANISTIC BASIS OF ANTIMICROBIAL RESISTANCE

Not surprisingly, bacteria have evolved sophisticated mechanisms of drug resistance to avoid killing by antimicrobial molecules, a process that has likely occurred over millions of years of evolution. Of note, resistance to one antimicrobial class can usually be achieved through multiple biochemical pathways, and one bacterial cell may be capable of using a cadre of mechanisms of resistance to survive the effect of an antibiotic. As an example, fluoroquinolone (FQ) resistance can occur due to three different biochemical routes, all of which may coexist in the same bacteria at a given time (producing an additive effect and, often, increasing the levels of resistance), i) mutations in genes encoding the target site of FQs (DNA gyrase and topoisomerase IV), ii) over-expression of efflux pumps that extrude the drug from the cell, and iii) protection of the FQ target site by a protein designated Qnr (see below for details on each of these mechanisms). On the other hand, bacterial species seem to have evolved a preference for some mechanisms of resistance over others. For example, the predominant mechanism of resistance to β-lactams in gram-negative bacteria is the production of β-lactamases, whereas resistance to these compounds in gram-positive organisms is mostly achieved by modifications of their target site, the penicillin-binding proteins (PBPs). It has been argued that this phenomenon is likely due to major differences in the cell envelope between gram-negatives and gram-positives. In the former, the presence of an outer membrane permits to “control” the entry of molecules to the periplasmic space. Indeed, most β-lactams require specific porins to reach the PBPs, which are located in the inner membrane. Therefore, the bacterial cell controls the access of these molecules to the periplasmic space allowing the production of β-lactamases in sufficient concentrations to tip the kinetics in favor of the destruction of the antibiotic molecule. Conversely, this “compartmentalization” advantage is absent in gram-positive organisms, although production of β-lactamases also seems to be successful in certain scenarios (e.g., staphylococcal penicillinase).

In order to provide a comprehensive classification of the antibiotic resistance mechanisms, we will categorize them according to the biochemical route involved in resistance, as follows: i)modifications of the antimicrobial molecule, ii) prevention to reach the antibiotic target (by decreasing penetration or actively extruding the antimicrobial compound), iii) changes and/or bypass of target sites, and iv) resistance due to global cell adaptive processes. Each of these mechanistic strategies encompasses specific biochemical pathways that will be described in detail in the reminder of the chapter. Of note, we will focus the discussion on the most relevant mechanisms giving examples that have relevant clinical impact.

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