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4.2 Medical Microbiology > Threat of Resistance and Their Mechanisms > Flashcards

Threat of Resistance and Their Mechanisms Flashcards

1
Q

Talk about the growing threat of antibiotic resistance

A

One of the top global public health and development threats
Estimated that bacterial AMR was directly responsible or 1.27 million global deaths and contributed to 4.95 million deaths in 2019
Thought to contribute to 50 million deaths by 2050
Rapidly increasing prevalence of MDR pathogens compicates treatment options

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2
Q

What is the main driver of resistance?

A

The misuse and overuse of antimicrobials in humans, animals and plants

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3
Q

What is mant by the dual threat of AMR?

A

Multi-drug resistance severly limits treatment options

Cross-infection facilitates spread and transmission

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4
Q

How does WHO combat AMR

A

In 2015 WHO launched the Global Action Plan on AMR in response to the growing AMR crisis

This lead to a need for a One Health approach

Who then launched the Global Antimicrobial Resistance and Use Surveillane System (GLASS)

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5
Q

What are the 5 objectives of the WHO global action plan

A

Improve awareness and understanding of antimicrobial resistance through effective communication, education and training

Strengthen the knowledge and evidence base through surveillance and research

Reduce the incidence of infection through effective sanitation, hygiene and infection prevenetion measures

Optimise the use of antimicrobial medicines in human and animal health

Develop the economic case for sustainable investment that takes account of the needs of al countries and to increase investment in new medicines, diagnostic tools, vaccines and other interventions

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6
Q

What does GLASS stand for?

A

Global Antimicrobial Resistance and Use Surveillance System

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7
Q

What has the last GLASS report in 2022 reported?

A

Highlights alarming resistance rates in 76 countries
42% third gen cephalosporin resistant E. Coli
35% methicillin resistant staph aureus
1 in 5 E. Coli UTIs show reduced susceptibility to ampicillin, co-trimoxazole, fluoroquinolones
K. pneumonia rising reliance on last resort antibiotics
Anticipated x2 surge in resistant to last resort antibiotis by 2035

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8
Q

Rate of resistant in E. Coli

A

42% third gen cephalosporin resistant E. Coli

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9
Q

Rate of resistance in S. aureus

A

35% methicillin resistant staph aureus

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10
Q

Rate of resistance in e. Coli UTIS

A

1 in 5 E. Coli UTIs show reduced susceptibility to ampicillin, co-trimoxazole, fluoroquinolones

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11
Q

How is the UN combatting resistance?

A

UN Genera Assembly held a high-level meeting on AMR in Septemeber 2024 to address the global threat of AMR

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12
Q

What is the WHO priority list and what is the point of is?

A

A list containing a catalogue of 15 families of bacteria that pose the greatest threat to human health

Intended to guide and promote research and development of new antibiotics

It classes bacteria as critical group, high group, medium group

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13
Q

What bacteria are part of the critical group according to WHO priority list
(4)

A

Enterobacterales -> Carbapenem resistant

Enterobacterales -> third gen cephalosporin resistant

Acinetobacter baumannii -> carbapenem resistant

M. tuberculosis -> rifampicin resistant

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14
Q

What bacteria are part of the high group according to WHO priority list

A

Salmonella typhi - fluoroquinolone resistant

Shigella species - fluoro resistant

E. faecium -> vancomycin resistant

P. aeruginosa -> carbapenem resistant

Non-typhoidal Salmonella -> fluoro resistant

N. gonorrhoeae -> third gen cephalosporin and/or fluoro resistant

S. aureus -> methicillin resistant

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15
Q

What bacteria are part of the medium group according to WHO priority list

A

Group A streptococci -> macrolide resistant
S. pneumoniae -> macrolide resistant
H. influenza -> ampicillin resistant
Group B streptococci -> penicillin resistant

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16
Q

What are the two classifications of resistance

A

Intrinsic resistance
Acquired resistance

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17
Q

What is intrinsic resistance?

A

The natural ability of the microorganism to resist specific antimicrobial agents, stemming from inherent biological characteristics rather than acquired mutations or gene transfer

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18
Q

What is acquired resistance?

A

This occurs when microorganisms gain the ability to resist agents through genetic mutations or the acquisition of resistance genes via horizontal gene transfer

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19
Q

How does intrinsic resistance affect the genotype of bacteria

A

There is a no change in genotype
Its a stable genetic property encoded in the chromosome, shared by all members of a genus

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20
Q

What are the two ways intrinsic resistance comes about?

A

Inaccessible Target

Target Not Susceptible to Antibiotic

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21
Q

Give an example of intrinsic resistance because of an inaccessible target

A

Anaerobic organisms that are inherently resistant to aminoglycosides because they lack an oxygen-dependent transport system to move the drgus across the cytoplasmic membrane

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22
Q

Give an example of intrinsic resistance because a targets not sussceptible to the antibiotic

A

Enterococci are inherently resistant to B-lactam antibiotics due to their low affinity of their PBP to them

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23
Q

How does acquired resistance affect the genome?

A

Arises by Alteration in genotype

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24
Q

What are the two methods of acquired resistance?

A

By Mutation through vertical gene transfer

Acquisition of exogenous genetic material through horizontal gene transfer

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25
How is resistance acquired through mutation via vertical gene transfer?
This occurs within the endogenous makeup of a bacterial cell This involves changes in the host chromosome, passed down to a daughter cell If resistant mutats survive they usually show only reduced susceptibility i.e. low level resistance Full resistance in a single step is rare
26
How is resistance acquired through acquisition of exogenous genetic material via horizontal gene transfer
Mechanisms include conjugation, transformation, or transduction New resistance genes are incorporated into the bacterial chromosome OR resistance genes are contained on a plasmid MGEs such as transposons and integrons enhance the transfer of resistance genes through various mechanisms MGEs provide bacteria numerous ways to spread and propagate resistance efficiently
27
What level of resistance is seen with vertical gene transfer, why is this?
Low level resistance This is because its rare to see full resistance mutations evolveing in just a single step -> way more likely to occur over multiple generations etc
28
What are the three mechanisms of horizontal gene transfer that can bring about resistance?
Conjugation Transformation Transduction
29
Where are resistance genes found in acquired resistance through horiontal gene transfer
Either incorporated into the bacterial chromosome or contained on a plasmid
30
What mobile genetic elements are responsible for acquired resistance through horizontal gene transfer?
Transposons and integrons
31
What is meant be selection of resistance?
Survival and proliferation of microorganisms with resistance traits under selective pressure, such as exposure to antimicrobial agents
32
How does selective resistance occur?
Antibiotics kill or inhibit susceptible bacteria allowing resistant strains to survive and multiply Even low concentrations of antibiotics can create selective environments that favour resistant bacteria
33
What are three sources of selective pressure?
Inappropriate antibiotic use e.g. overprescription or misuse of antibiotics in healthcare settings Agricultural Use e.g. antibiotics used in livestock for growth promotion or disease prevention Environmental Contamination e.g. antibiotic residues in water, soil and wastewater
34
What are the four main mechanisms of resistance?
Enzymatic inactivation Modification of target sites Efflux pumps Reduced permeability
35
What two mechanisms of resistance often go hand in hand?
Efflux pumps and reduced permeability
36
What is the mechanism behind enzymatic inactivation as a form of resistance
Bacterial production of specific enzymes that inactivate antibiotics These enzymes hydrolyse, acetylate or otherwise modify antibiotics, preventing them from interacting effectively with bacterial targets
37
What are the three most common methods on enzymatic inactivation
Hydrolysis Group transfer/acetylation Redox process
38
Give two examples of hydrolysis as a methood of antibiotic inactivation
B-lactamase enzymes on B-lactams Esterase on Macrolides
39
Give an example of group transfer as a methood of antibiotic inactivation
transferase-mediated resistance against aminoycosides Most common in enterobacterales and enterococci
40
Give an example of a redox reaction as a method of enzymatic inactivation of antibiotics
Tetracycline modified into 11a-hydroxy-tetracycline -> addition of O2
41
Talk about B-lactamase enzymes
These can degrade the B-lactam ring of penicillins, cephalosporins and carbapenems This renders these drugs ineffective
42
In general where are B lactamase enzymes most commonly found
Enterobacteriaceae
43
Talk abut penicillinases
B-lactamases against penicillins Mainly in gram positives
44
Talk about cephalosporin b-lactamase enzymes
ESBLs Mostly in GNBs
45
Talk about carbapenemases
B-lactamases against carbapenems Mostly in enterobacteriacae and pseudomonas
46
Talk about the prevalence of B-lactamases
Prevalence of ESBLs and CPEs is concerning especially in hospital settings where these pathogens contribute to healthcare-associated infections
47
Talk about acetylate/group transfer mediated resistance
Aminoglycoside resistance Transferase mediated resistance Commonly associated with enterobacterales and enterococci
48
What are the three therapeutic implications of enzyme mediated resistance
Compelled to rely on B-lactamase inhibitors in combination with B-lactam antibiotics to counteract resistance Evolution of carbapenemase-producing organisms has diminished the efficacy of even these combinations, this pushes clinicians towards alternatives like colistin or polymyxins which are toxic The clinical burden of treatening infections with these last-resort antibiotics has heightened, demanding careful patient monitoring and increasing healthcare costs
49
What are our two main B-lactamase inhibitors?
Clavulanic acid or tazobactam NB: new resistance to these
50
How does modification of target sites work as a mechanism of resistance
Bacteria can evade antibiotics by mutating or modifying the drug's target site within the bacterial cell This reduces the binding affinity of the antibiotic, this allowing the pathogen to survive Altered target sites often arise from point mutations or horizontal gene transfer of resistance genes
51
Through what two ways can altered target sites arise?
Point mutations or horizontal gene transfer
52
What are the four ways that a bacteria can modify its target site?
Alteration of target enzyme e.g. peniciliin binding proteins altered cell wall target alteration of ribosomal target sites production of auxotrophs bypass inhibited steps
53
Give an example of alteration of target enzymes inducing resistance against penicillins
PBPs are enzymes located on the outer surface of the bacterial cytoplasm These catalyse the cross-linking of peptidoglycan in the bacterial cell wall These also serve as the target sites for B-lactam antibiotics Thus mutations in these PBPs lead to PBPs losing afinity for B-lactam antibiotics Reduced number of PBPs can also further limit the bindin of these B-lactam drugs (usually see both together)
54
What are PBPs actually?
Enzymes such as transglycosylases and transpeptidases
55
What is peptidoglycan also known as?
Murein
56
Give five specific examples of alteration of a target enzyme
Methicillin resistance in S. aureus Penicillin resistance in PNSP Reduced cephalosporin susceptibility in N. gonorrhoeae Quinolone resistance Rifampicin resistance
57
Talk about MRSA as an example of an altered target enzyme mechanism of resistance
Acquisition of the mecA gene which encodes a modified PBP2a which has reduced affinity for B-lactam antibiotics This modification renders all B-lactam antibiotics ineffective against MRSA
58
Talk about PNSP as an example of an altered target enzyme mechanism of resistance
Altered PBPs cause reduced susceptiblity to penicillin in certain S. pneumoniae strains
59
Talk about N. gonorrhoeae as an example of an altered target enzyme mechanism of resistance
Altered PBP2 associated with reduced susceptibility to ceftriaxone
60
Talk about quinolone resistance as an example of an altered target enzyme mechanism of resistance
Quinolones inhibit DNA synthesis, target bacterial DNA gyrase Mutations in the gyrA gene (encoding NA gyrase) lead to broad-spectrum resistance against all fluoroquinolones
61
Talk about Rifampicin resistance as an example of an altered target enzyme mechanism of resistance
Rifampiin inhibits RNA synthesis by binding to the B-subunit of RNA polymerase, thereby blocking mRNA synthesis Mutations that alter the B-subuit of RNA polymerase reduce the drugs binding affinity, resulting in resistance to rifampicin
62
How does alteration of cell wall precursor targets induce resisitance
Resistance arises through acquisition of genes encoding ligases which synthesis abnormal pentapeptide precursors with altered termini, reducing the binding affinity of antibiotics such as glycopeptides
63
Give an example of where alteration of cell wall precursor targets induces resistance
Glycopeptide resistance in enterococci, such as VREs
64
Explain glycopeptide resistance as an exaple of alteration of cell wall precursor targets as a mechanism of resistance
Vancomycin and teicoplanin bind to the D-ala-D-ala termin of pentapeptide chains in peptidoglycan subunits, inhibiting the cross-linking of the bacterial cell wall
65
Give two examples of alteration of ribosomal target sites as a mecahnism of acquired resistance
Amionglycoside resistance e.g. streptomycin resistance in mycobacterium tuberculosis Macrolide-Lincosamide-Streptogramin MLS Resistance
66
Talk about aminoglycoside resistancfe as an example of alteration of ribomsal target sites
Aminoglycosides bind to multiple sites on the ribosom to block protein synthesis Resistance occurs through the production of altered ribosomal binding proteins e.g. streptomycin resistance in MTB
67
Talk about macrolide-lincosamide-streptogramin resistance as an example of alteration of ribomsal target sites
Drugs like erythromycin and clindamycin bind to the 50S ribosomal sunit interfering with protein synthesis Production of ribosomal enzymes with reduced macrolide binding affinity incur resistance
68
What does MLS resistance stand for?
Macrolide-Lincosamide-Streptogramin resistance
69
Give two examples of resistance whereby production of auxotrophs bypass inhibited steps
Sulphonamide and trimethoprim -> both drugs work by competitively inhibiting the folic acid metabolic pathway which is essential for bacterial survival
70
Talk about sulphonamide resistance as an example of auxotroph production
Acquired resistance arises from the production of an altered dihydropteroate synthase enzyme with reduced affinity for sulphonamides
71
Talk about trimethoprim resistance as an example of auxotroph production
Resistance develops due to the production of a new dihydrofolate reductase enzyme that has reduced susceptibility to trimethoprim
72
Talk about efflux pumps as a mechanism of resistance
Active efflux is a reconised common mechanism of resistance Normal levels of efflux contribute to low level intrinsic resistance but bacteria can increase expression for high level Resistance occurs due to active extrusion of drugs from the cell This extrusion is mediated by multi-drug efflux pumps Efflux pumps are categorised into five distinct protein superfamilies
73
What is the function of efflux systems
They facilitate the removal of various secondary metabolites including antibiotics They may be specific to a single substrate or broad spectrum expessling diverse compoints including antibiotics from multiple different classes (MDR)
74
Talk about the expression of efflux pumps
Overexpression of efflux pumps or amino acid substitutions enhances pump efficiency, potentially leading to high-level multidrug resistance Increased efflux pump activity may be an initial step in a bacterium's progression to full resistance Multi subunit efflux pumps are often encoded on the bacterial chromosome
75
What is the effect of elevated efflux activity
Reduces intracellular antimicrobial levels enabling bacterial survival and facilitating the accumulation of additional resistance mutations
76
Where are multi subunit efflux pumps encoded?
Encoded on the bacterial chromosome
77
What are the five categories of efflux pumps?
Major Facilitator Superfamily (MFS) Resistance-Nodulation-Division (RND) Small Multidrug Resistance (SMR) ATP-Binding Casette (ABC) Multidrug and toxic compound extrusion (MATE)
78
Talk about major facilitator superfamily of efflux pumps
MFSs found in E. Coli and S. aureus Efflux antibiotics such as tetracyclines as well as dyes and sugars
79
Talk about the resistance nodulation division of efflux pumps
RNDs found in P. aeruginosa and E. Coli Efflux antibiotics such as beta lactams and fluoroquinolones as well as detergents
80
Talk about the small multidrug resistance family of efflux pumps
SMRs found in E. Coli and M. tuberculosis Efflux disinfectants and antiseptics
81
Talk about the ATP-binding cassette family of efflux pumps
ABCs found in S. aureus and E. Coli Efflux antibiotics such as macrolides and peptides
82
Talk about the multidrug and toxic compound extrusion family of efflux pumps
MATEs found in Vibrio cholerae and P. aeruginosa Efflux antibiotics such as fluoroquinolones and organic cations
83
Talk about efflux pumps in GNBS
Efflux pumps in GNBs often span both the inner and outer membranes This enables efficient extrusion of antibiotics directly into the external environment RND pumps are major contributors to MDR in HAI caused by GNBS Many of these pumps handle a variety of antibiotics, biocides and toxic compounds making infections very difficult to treat
84
Why are we most concerned with RND family efflux pumps in GNBs
These pumps often work in conjunction with other resistance mechanisms such as enzyme degadation or permeability changes
85
Talk about spread of resistance and efflux pumps in GNBs
Efflux pumps in pathogens like K. pneumoniae and A. baumannii are associated with global dissemination of MDR strains
86
Talk about the role of efflux pumps in lastresort drug resistance
Pumps such as KpnEF in K. pneunoniae are linked to resistance against last-resort antibiotics like tigecycline
87
Talk about efflux pumps in gram positives
Resistance mediated by efflux transporters located in the cytoplasmic membrane The Major Facilitator Superfamily is the key efflux pump family in gram positives Efflux pumps can bring about intrinsic or acquired resistance in gram positives
88
Talk about resisistance mediated by efflux pumps in gram positives
Seen in S. aureus and S. pneumonia intrinsic and transferable resistance Resistance to a wide range of antimicrobials and biocides
89
What are the two types of efflux pumps in gram positives, what is the importance of these
Plasmid encoded efflux pumps which facilitate horizontal spread of resistance Chromosomally encoded pumps provide intrinsic resistance to key antibiotics
90
Give two exampls of plasmid encoded efflux pumps in gram positives
QacA/B MefA
91
Give three examples of chromosomally encoded efflux pumps in gram positives
NorA NorB NorC
92
How does multidrug resistance come about, in relation to porins?
Porin alterations o ften coexist with other resistance mechanisms such as eflux pumps or enzymatic degradation, making infections much more difficult to treat
93
In what four ways can porins induce antibiotic resistance?
Reduced permeability leads to resistance Mutations or loss of porins result in resistance Altered porins slow drug penetration Limited porin availability reduces efficacy
94
Give an example of where reduced porin permeability leads to resistance
Normally beta lactams diffuse through general porins e.g. OmpF But reduced permeabiblity leads to resistance
95
Give an example of where mutations or loss of porins result in resistance
Carbapenems utilise specific porins such as OprD in P. aeruginosa but mmumtations in these or a loss of these porins results in resistance
96
Give an example of where altered porins slow drug penetration
Fluroquinolones normally diffuse through porins into the cytoplasm altering these porins slows down the penetration of the drug
97
Give an example of where limited porin availability reduces efficacy
Aminoglycosides enter via porins and interact with ribosomes Limiting porin availability prevents entry
98
Talk about carbapenem resistance induced by porins
Loss or modification of specific porins like OmpK36 in K. pneumonia or OprD in P. aeruginosa is a hallmark of carbapenem resistance
99
Talk about porin induced resistance and their relevance in HCAI
Pathogens like Acinetobacter baumannii and K. pneumoniae with altered porins are common causes of HCAI leading to treatment failures
100
How do different mechanisms of resistance work together
1. individual class of drugs inactivated by different mechanisms 2. individual organism employs different mechanisms to generate resistance to single drug/different classes of drugs -> these mechanisms interact todetermine actual level of resistance
101
What is synergistic resistance?
Whereby most clinically signigicant bacteria employ at least two or more resistant mechanisms for the same antibiotic class A combination of mechanisms that leads to higher levels of resistance, often termed extensivelt drug-resistant or multidrug resistant
102
What is cross-class resistance
Whereby one mechanisms has affects across more than one class of antibiotics e.g. efflux pumps and permeability changes often provide cross-class resisistance impacting multile antibiotic classes simultaneously
103
Talk about synergistic resistance in K. pneumoniae
Resistance to B-lactams by multiple mechanisms Beta lactamase production e.g. ESBLs, KPC Porin loss to reduce permeability -> porin Ompk35/OmpK36 are altered Efflux pumps to actively remove beta-lactams from the cell
104
Talk about synergistic resistance in P. aeruginosa
Resistance against fluoroquinolones through multiple mechanisms: - efflux pumps encoded by MexAB-OprM system removes fluoros - target modification encoded by mutations in DNA gyrase (gyrA) or topoisomeras IV (parC) - outer membrane changes to limit drug penetration
105
Talk about synergistic resistance in S. aureus
Resistance to macrolides through multiple mechanisms: -target modification - ribosomal methylation via erm genes (ermA or ermC) reduces macrolide binding to 50S ribosomal subunit -efflux pumps: MsrA pump actively expels macrolides
106
Conclusions on resistance mechanisms
The molecular mechanismms underlying bacterial resistance highlight the formidable challenge facing modern medicine Each resistance mechanism - enzymatic degradation, target modification, efflux pumping, or reduced permeability - constrains available treatment options and necessitates new approached in both clinical management and drug development Multifaceted approach combining clinical vigilance, therapeutic innovation and policy support is essential to manage and mitigate the impact of resistance effectively

4.2 Medical Microbiology (20 decks)

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