Paper
English
“ANTIBIOTICS RESISTANCE”
BY:
NAME : ASTRIANI SAUH SATAONG
NIM : 821423026
CLASS : S1-C FARMASI
SUPPORTING LECTURER: Dr. Suleman Bouti, S.Pd,
M.Hum
BACHELOR OF PHARMACY STUDY PROGRAM
PHARMACEUTICAL DEPARTMENT
FACULTY OF SPORTS AND HEALTH
GORONTALO STATE UNIVERSITY
2023
FOREWORD
The use of antibiotics has been one of the most important milestones in the development of
modern medicine, providing protection against bacterial infections which in the past were
often fatal. Antibiotics have saved millions of lives and significantly increased human life
expectancy. However, this great success has been accompanied by a great challenge, namely
antibiotic resistance.
Antibiotic resistance is a serious threat to the effectiveness of antibiotics. This condition
occurs when the bacteria that cause the infection develop resistance to the antibiotics that are
supposed to kill them. As a result, previously effective antibiotics are no longer useful in
treating bacterial infections. Antibiotic resistance has become a global issue affecting health
care systems, costs, and life expectancy.
This paper aims to present a deeper understanding of the importance of rational use of
antibiotics as an effort to prevent increasing antibiotic resistance. In this paper, we will
describe what is meant by antibiotic resistance, the main causes of resistance, the principles
of rational use of antibiotics, the consequences of antibiotic resistance, and the steps that can
be taken to overcome this problem.
We hope that this paper will provide useful information and raise awareness about the
important role each individual plays in preventing antibiotic resistance. Every action we take,
whether as patients, doctors or other health stakeholders, can help keep antibiotics effective
and contribute to the global effort to fight antibiotic resistance.
The author would like to thank all those who have contributed to the research and writing of
this paper. We hope that this paper will be a useful source of knowledge for readers and
support our common struggle against antibiotic resistance.
Gorontalo, September 2023
Astriani Sauh Sataong
LIST OF CONTENTS
FOREWORD............................................................................................................................ii
LIST OF CONTENTS............................................................................................................iii
CHAPTER 1............................................................................................................................iv
INTRODUCTION...................................................................................................................iv
1.1 Background..........................................................................................................iv
2.1 Formulation of the problem...................................................................................v
3.1 Writing Purpose.....................................................................................................v
CHAPTER II............................................................................................................................v
DISCUSSION...........................................................................................................................v
2.1 Basic Concepts of Antibiotics...............................................................................v
2.2 Genetic Basic of Anti-microbial Resistance.........................................................vi
2.3 Genetic Basis of Anti-Microbial Resistance.......................................................vii
A. Modification of Antibiotic Molecules.........................................................................vii
B. Changes in Antibiotic Chemistry.................................................................................vii
A.Decreasi Permeability..........................................................................................viii
B.Exhaust pump.........................................................................................................ix
CHAPTER III...........................................................................................................................x
CLOSING.................................................................................................................................x
3.1 Conclusion.............................................................................................................x
BIBLIOGRAPHY...................................................................................................................xi
CHAPTER 1
INTRODUCTION
1.1 1.1 Background
Starting in the 1940s, mass production of antibiotics involved growing
microorganisms on an industrial scale to harvest their metabolic products. Unfortunately,
antibiotic use selects for resistance on the response scale. The turn to the study of antibiotic
resistance in microbiology and medicine is examined, with a focus on the realization that
individual therapy targeted at a single pathogen in an individual's body is an environmental
event that influences bacterial evolution far beyond the body. In turning to the biological
manifestations of antibiotic use, the sciences understand the material outcome of their own
concepts previously. Archiving work with stored soil and clinical samples produces records
described here as 'historical biology': the physical registration of human history in the lives of
bacteria. Antibiotic resistance is a timely topic for epidemiologists, microbiologists and
physicians; and health economists and public health officials focused on the practical
problem of what to do in the face of a crisis. At the same time, antibiotic resistance presents a
critical issue of what to think about inside and outside biomedical science. Antibiotics kill by
selective toxicity, disrupting microbial structures or processes that are not present in human
cells.
Their production is driven by the theory of antibiosis: humans utilizing substances
created by microbes in a conflicting battle for space and resources. Humans make antibiotics
by cultivating microbes, chemically tweaking the microbial metabolites, and replicating them
with synthetic antibiotics. Antibiotic resistance arises when microbes acquire the capacity to
evade these drugs. In the history of biology, ideas about bacteria change. In historical biology,
bacterial ideas change. Today's bacteria are not the bacteria of yesterday, whether the changes
are cultural, genetic, physiological, ecological, or medical. Today's bacteria have different
plasmids and properties and relatedness and capacity and distribution and temporality than
bacteria before modern antibiotics. It is not even clear that 'bacteria' remains the only or most
prominent category for thinking about antibiotic resistance. This biological material, devising
its own ontology, is historically and culturally – and materially – specific to late
industrialism, produced within and by previous modes of knowledge (Jose M. Munita, 2016).
2.1 2.1 Formulation of the problem
What is the basic concept of antibiotic resistance mechanisms?
What are the basics of antibiotic resistance?
3.1 3.1 Writing Purpose
To find out the mechanism of antibiotic resistance, and to fulfill applied English
assignments.
CHAPTER II
DISCUSSION
4.1 2.1 Basic Concepts of Antibiotics
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
necessary for the development of complex medical approaches such as cutting-edge surgical
procedures, solid organ transplantation and the management of patients with cancer, among
others. Unfortunately, the marked increase in antimicrobial resistance among common
pathogenic bacteria now threatens these therapeutic achievements, 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. To understand the problem of antimicrobial resistance, it is useful to discuss
several relevant concepts.
First, antimicrobial resistance is ancient and is an expected result of the interactions of many
organisms with their environment. Most antimicrobial compounds are naturally produced
molecules, and, as such, cohabiting bacteria have developed mechanisms to overcome their
actions in order to survive. Thus, these organisms are often considered "intrinsically" resistant
to one or more antimicrobials. However, when discussing the antimicrobial resistance
conundrum, bacteria harboring intrinsic resistance determinants are not the main focus of the
problem. In contrast, in clinical settings, we usually refer to the expression of “acquired
resistance” in bacterial populations that are initially susceptible to antimicrobial compounds.
As will be discussed later in this chapter.
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) depends primarily on the in vitro activity of the antibiotic against a sufficiently
large sample of bacteria, combined with several pharmacological parameters (e.g., blood and
antimicrobial infection site concentrations, among others). Thus, when treating antibiotic-
resistant bacteria, interpretation of susceptibility patterns may vary according to the clinical
scenario and availability of treatment options. For example, the concentrations of gentamicin
achieved in urine may be high enough to treat lower urinary tract infections caused by
organisms reported to be resistant to gentamicin. Similarly, different penicillin breakpoints
have been established for Streptococcus pneumoniae depending on whether the isolate causes
meningitis vs. other types of infection, taking into account the level of drug that actually
reaches the cerebrospinal fluid. Additionally, 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 deep-seated infections caused by cephalosporin-susceptible S. aureus. So, in the
following sections, we will focus on molecular mechanisms and biochemistry of bacterial
resistance, which describes specific situations frequently encountered in clinical practice.
5.1 2.2 Genetic Basic of Anti-microbial Resistance
Bacteria have extraordinary genetic plasticity that allows them to respond to a wide variety of
environmental threats, including the presence of antibiotic molecules that can endanger their
existence.
A. Drug Resistance
In this scenario, a subset of bacterial cells originating from a susceptible population
develops mutations in genes that affect the activity of the drug, resulting in cell
viability being maintained by the presence of the antimicrobial molecule. Once
resistant mutants emerge, antibiotics eliminate the susceptible population and resistant
bacteria dominate. In many cases, mutational changes that cause resistance are costly
to cell homeostasis (i.e., decreased fitness) and are only maintained if necessary in the
presence of antibiotics. In general, mutations resulting in antimicrobial resistance alter
the action of antibiotics through one of the following mechanisms,
i) modification of antimicrobial targets (lowering affinity for the drug)
i) decreased drug absorption,
ii) activation of efflux mechanisms to expel harmful molecules, or
iv) global changes in important metabolic pathways through modulation of regulatory
networks. Thus, the resistance that arises due to acquired mutational changes is
diverse and varies in complexity. In this chapter, we will provide several examples of
antimicrobial resistance that arises through mutational changes.
B. Horizontal Gene Tranfer
The acquisition of foreign DNA material through HGT is one of the most important
drivers of bacterial evolution and is often responsible for the development of
antimicrobial resistance. Most antimicrobial agents used in clinical practice are (or are
derived from) products naturally found in the environment (mostly soil). As
mentioned previously, bacteria that share an environment with these molecules have
intrinsic genetic determinants of resistance and there is strong evidence to suggest that
such “environmental resistors” are a productive source for the acquisition of antibiotic
resistance in clinically relevant bacteria. Furthermore, this genetic exchange has been
implicated in the spread of resistance to many commonly used antibiotics. Classically,
bacteria acquire external genetic material through three main strategies,
i ) transformation (incorporation of naked DNA),
ii ) transduction (phage-mediated) and,
iii) conjugation (bacterial "sex").
Transformation may be the simplest type of HGT, but only a handful of clinically
relevant bacterial species are capable of “naturally” incorporating naked DNA to
develop resistance.
The emergence of resistance in hospital settings often involves conjugation, a highly
efficient method of gene transfer that involves cell-to-cell contact and is most likely to
occur at high levels in the human gastrointestinal tract under antibiotic treatment. As a
general rule, conjugation uses mobile genetic elements (MGEs) as vehicles for
sharing valuable genetic information, although direct transfer from chromosome to
chromosome has also been well characterized (9). The most important MGEs are
plasmids and transposons, both of which play an important role in the development
and spread of antimicrobial resistance among clinically relevant organisms. Finally,
one of the most efficient mechanisms for accumulating antimicrobial resistance is
represented by integrons, which are site-specific recombination systems capable of
recruiting scaffolds. read opens in the form of a mobile cassette gene. Integrons
provide an efficient and rather simple mechanism for the addition of new genes to
bacterial chromosomes, along with the machinery necessary to ensure their
expression; a powerful strategy of genetic exchange and one of the main drivers of
bacterial evolution. For details on the mechanisms of HGT, the reader is referred to a
recent state-of-the-art review (10).
6.1 2.3 Genetic Basis of Anti-Microbial Resistance
Not surprisingly, bacteria have developed sophisticated drug resistance mechanisms to avoid
being killed by antimicrobial molecules, a process that has likely occurred over millions of
years of evolution. Of note, resistance to one class of antimicrobial can usually be achieved
through multiple biochemical pathways, and a single bacterial cell may be capable of
employing a range of resistance mechanisms to survive the effects of the antibiotic. To
provide a comprehensive classification of antibiotic resistance mechanisms, we will
categorize them according to the biochemical routes involved in resistance. ,as follows:
i) modification of antimicrobial molecules,
ii) prevention of reaching the antibiotic target (by reducing penetration or actively extruding
the antimicrobial compound),
iii) alteration and/or bypass of target sites, and
iv) resistance due to global cellular adaptive processes. Each of these mechanistic strategies
includes specific biochemical pathways that will be explained in detail in this chapter's
reminder. Of note, we will focus the discussion on the most relevant mechanisms by
providing examples that have relevant clinical impact.
A. Modification of Antibiotic Molecules
One of the most successful bacterial strategies for dealing with the presence of antibiotics is
to produce enzymes that deactivate the drug by adding certain chemical moieties to the
compound or that destroy the molecule itself, making the antibiotic unable to interact with its
target.
B. Changes in Antibiotic Chemistry
One of the best examples of resistance through drug modification is the existence of
aminoglycoside modifying enzymes (AMEs) which covalently modify the hydroxyl or amino
groups of aminoglycoside molecules. Several AMEs have been described to date and they
have become the main mechanism of aminoglycoside resistance worldwide.
C. Destruction of Antibiotic Molecules
The main mechanism of β-lactam resistance relies on the destruction of these compounds by
the action of β-lactamases. These enzymes destroy the amide bond of the lactam-ring,
rendering the antimicrobial ineffective. -lactamases were first described in the early 1940s,
one year before penicillin was introduced to the market, however, there is evidence of their
existence for millions of years (15,16). Infections caused by penicillin-resistant S. aureus
became clinically relevant after penicillin became widely available and the resistance
mechanism was discovered to be a plasmid-encoded penicillinase that was readily transmitted
between S. aureus strains, resulting in the rapid spread of resistance traits ( 17 ). To overcome
this problem, new β-lactam compounds with a broader spectrum of activity and lower
susceptibility to penicillinase (such as ampicillin) were produced. However, during the 1960s
a new plasmid-encoded -lactamase capable of hydrolyzing ampicillin was discovered among
gram-negatives (called TEM-1 after the name of the patient in whom it was originally
discovered [Temoneira]. Since then, the development of a new generation of -lactams has
been systematically followed by the emergence of the enzyme rapid destruction of new
compounds that reach the market, in a process that is a prime example of antibiotic-driven
adaptive bacterial evolution. Genes encoding β-lactamases are generally called γ-lactamases
followed by the name of the specific enzyme (e.g. KPC) and they have been found in
chromosomes or localized in MGE as part of the accessory genome. These genes can also be
found forming part of integrons, a situation that facilitates their spread. In terms of their
expression, transcription of these genes may be constitutive or may require an external signal
to induce their production.2.4 Decreased penetration and efflux of antibiotics.
7.1 A.Decreasi Permeability
Many antibiotics used in clinical practice target intracellular bacteria or, in the case of gram-
negative bacteria, located in the cytoplasmic membrane (inner membrane). Therefore,
compounds must penetrate the outer membrane and/or cytoplasm to exert their antimicrobial
effects. Bacteria have developed mechanisms to prevent antibiotics from reaching
intracellular or periplasmic targets by reducing the uptake of antimicrobial molecules. This
mechanism is especially important in gram-negative bacteria (for the reasons mentioned
above), limiting the entry of substances from the external environment. In fact, the outer
membrane acts as the first line of defense against the penetration of several toxic compounds,
including some antimicrobial agents. Hydrophilic molecules such as -lactams,37). A prime
example of the efficiency of this natural barrier is the fact that vancomycin, a glycopeptide
antibiotic, is not active against gram-negative organisms due to its lack of penetration through
the outer membrane. Likewise, the low inherent susceptibility of Pseudomonas and
Acinetobacter baumannii to β-lactams (compared with Enterobacteriaceae) may be explained,
at least in part, by a reduction in the number and/or expression of different porins (38).
Several types of porins have been described, and they can be classified according to their
structure ( trimeric vs. monomeric), their selectivity and expression regulation. Among the
best characterized porins, the three major proteins produced by E. coli (known as OmpF,
OmpC and PhoE) and P. aeruginosa OprD (also known as D2 protein) are classic examples of
porin-mediated antibiotic resistance. Porin changes can be achieved by 3 general processes,
i) shift in the type of porin expressed,
ii) changes in porin expression levels, and
iii) impaired porin function. Importantly, changes in permeability through one of these
mechanisms often result in low-level resistance and are often associated with other resistance
mechanisms, such as increased expression of efflux pumps.
8.1 B.Exhaust pump
The production of complex bacterial machinery capable of removing toxic compounds from
cells can also result in antimicrobial resistance. Descriptions of efflux systems capable of
pumping tetracycline out of the E. coli cytoplasm date back to the early 1980s and were
among the first to be described ( 43 ). Since then, many classes of efflux pumps have been
characterized in both gram-negative and gram-positive pathogens. These systems may be
substrate specific (for certain antibiotics such as determinants for tetracyclines and genes for
macrolides in pneumococci) or with broad substrate specificity, which is usually found in
MDR bacteria (44). These resistance mechanisms affect various classes of antimicrobials
including protein synthesis inhibitors, fluoroquinolones, β-lactams, carbapenems, and
polymyxins. Genes encoding efflux pumps can be found in the MGE (as described initially
for genes) or within the chromosome. Importantly, chromosomally encoded pumps may
explain the inherent resistance of some bacterial species to certain antibiotics. Tetracycline
resistance is one of the classic examples of efflux-mediated resistance, in which the Tet efflux
pump (belonging to the MFS family) extrudes tetracycline using proton exchange as an
energy source.
CHAPTER III
CLOSING
9.1 3.1 Conclusion
The use of antimicrobials in clinical practice is a recent development in history compared to
the emergence of bacterial organisms on our planet. Therefore, the development of antibiotic
resistance should be seen as a “normal” adaptive response and a clear manifestation of the
principles of Darwinian evolution. Arguably, the application of antimicrobial therapy in
clinical practice has been one of the most successful advances of modern medicine, paving
the way for complex and highly sophisticated medical interventions that have made it
possible to significantly extend the life span of populations worldwide. To survive, bacteria,
in a process likely suppressed by the increased use of antimicrobials in clinical practice, have
developed complex and creative strategies to evade antibiotic attack. Antibiotic resistance has
grown rapidly in recent decades to become one of the greatest public health threats of the 21st
century. Indeed, infections that cannot be treated due to multidrug resistance of the infected
organism have become more common in the clinical setting. This dire scenario is exacerbated
by the lack of antibiotic research and development. The “golden” pipeline of antibiotic
discovery (1960s and 70s) quickly dried up as the identification of new compounds became
more challenging. Big pharma is concentrating their efforts on other more profitable and
beneficial areas, leaving behind a growing wave of resistance. If we are to overcome this
problem, research and development efforts need to be greatly increased and supported. A
complete understanding of the mechanisms by which bacteria become resistant to antibiotics
is essential for designing new strategies to combat the threat of resistance. We need to
develop antibiotics with the understanding that microorganisms will respond to them and
resistance will develop (an evolutionary fact). Therefore, efforts to develop antibiotics and
study resistance mechanisms must be carried out continuously, tenaciously and steadily. This
will likely be a long-term “war” against living creatures with a great ability to adapt and
survive. Efforts to develop antibiotics and study resistance mechanisms must be continuous,
tough and steady. This will likely be a long-term “war” against living creatures with a great
ability to adapt and survive. Efforts to develop antibiotics and study resistance mechanisms
must be continuous, tough and steady. This will likely be a long-term “war” against living
creatures with great abilities to adapt and survive.
BIBLIOGRAPHY
Mechanisms of Antibiotic Resistance: Microbiol Spectr
Author Manuscrapt; Available in PMC 2016 October 01.
Download from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888801/Munita.
J.M., (2016).
Mechanisms of Antibiotic Resistance. Author
Manuscript. Colombia: Universidad El Bosque
