Micro lecture 10

Question 1

state facts about Antibacterial Resistance

Answer 1

An increasing problem

Once resistance originates in a population it can be transmitted to other bacteria

A particular type of resistance mechanism is not necessarily confined to a single class of drugs

Resistance mutations arise spontaneously and are then selected

Question 2

state more facts about resistance

Answer 2

ALL antibiotic use drives resistance – whenever and wherever a microbial population is exposed

Resistant infection is rarely developed during most short-term treatments (TB, HIV are different). They can be “unmasked” though

(Due to the greater numbers) Resistance USUALLY originates among the recipient’s normal flora (note recipient can be human, animal, sewage system, …)

Once present, It can then be “bred” due to improved survival when exposed to selection pressure

Resistance genes can be spread between cells, even between different species

Question 3

how does Overgrowth of resistant organisms occur?

Answer 3

1. Many billions of cells dividing “exponentially” and sometimes mutating
2. “One” resistant cell (acquired or mutated)
3. Population is exposed to drug
4. Resistant progeny grow through

Question 4

explain the mechanism of drug resistance

Answer 4

Prevent entrance of drug
drug can’t bind to or penetrate pathogen
bacterial decrease in permeability

Pump drug out

Inactivation of drug
chemical modification of drug by pathogen

Alteration of target enzyme or organelle
Use of alternative pathways or increased production of target metabolite

Question 5

what are the Six potential pitfalls of β-lactams – resistance

Answer 5

Peptidoglycan
Some organisms do not use peptidoglycan

Penetration into infected cells
β-lactams penetrate poorly into host cells
(ineffective against intracellular pathogens)

Porins in G-ve bacteria
Needed to gain access to PBPs.
“Porin-poor” strains exist

Pumps
Efflux pumps transport antibiotics back out of the cell (most effective for G –ve as they can pump out of the outer membrane)

PBPs (Penicillin-binding proteins)
Low affinity binding (may be acquired or intrinsic - vary between organisms anyway)
(“acquired” includes MRSA, among others)

Penicillinases (β-lactamases)
Enzymes that degrade β-lactam ring; descended from PBPs. Again many variations

Question 6

what are the Origins of Antibacterial Resistance

Answer 6

Origin:
Most antimicrobials are of microbial origin, so intrinsic resistance MUST exist

Even 1 per billion divisions or more is statistically quite likely; then all that’s needed is refinement of that characteristic to make it “worth” keeping

Question 7

how does Transmission of Resistance happen?

Answer 7

Chromosomal genes:
Passed on during cell division to “all” progeny

Mobile genetic elements:
(plasmids, transposons, integrons)
Genes on these can move within and / or be freely exchanged between bacteria

Gene cassettes:
“sets” of related or unrelated resistance genes
can exist as separate genetic elements or can be part of transposon, integron or chromosome

Question 8

how to Delay emergence of resistance

Answer 8

Use drugs only when necessary :
- and don’t give them to healthy livestock !

Achieve adequate concentrations (MPC):
- this will stop your pathogen becoming resistant but there are many other species in/on the body

Consider two or more drugs at same time (occasionally):
- some drugs can be beaten by a single mutation

Possible future solutions:
Continued development of new drugs
Vaccination
Use of bacteriophages to treat bacterial disease

Question 9

what is the One management strategy for antibacterials

they are 10.

Answer 9

Revise G- vs. G+ cell wall

Revise peptidoglycan structure and synthesis

Revise Penicillin-binding proteins (PBP) activity

Understand interplay of PBP activity, b-lactam antibiotics, b-lactamases, b-lactamase inhibitors

β-lactams (pencillin evolution / cephalosporins generations / carbapenems / monobactams)

glycopeptides / fosfomycin / bacitracin (Peptidoglycan synthesis inhibitors)

Cell wall disruptors (daptomycin / colistin)

Bacterial protein synthesis (transcription/translation simultaneous, ribosome structure, P/A/E sites, cycling of initiation/elongation/termination)
Different classes of protein synthesis inhibitors

Metabolic antagonists

Nucleic acid synthesis inhibitors

Origins of antibacterial resistance / transfer / prevention

Read WHO report and have major classes (now) + next 10-20 years of antibiotics