Antibiotics

antibiotics - naturally occuring substances with antibacterial effects

chemotherapy (p.ehrlich) - orig. treatment of microbial (bacterial) diesases with synthetic substances, which inhibit bacterial grwoth or kill microorganism

natural occurring agents - low molecular weight metabolites of fungi or bacteria with antibacterial effects against other microorganisms

semi-synthetic agents - chemically modified in order to improve pharmacological properties

synthetic agents - generated completely in-vitro

penicilium notatum: now p. chrysogenum

1945 - fleming, chain, florey are awarded the nobel price

ß-lactam ring in strucutre is important -> inhibit bacteria cell wall biosynthesis

ß-lactam: most widely used AB in the NHS

all contain a beta lactam ring

e.g. penicilins such as amoxicilin and flucoxacilin. cephalosporins such as cefalexin.

mode of acion - inhibit baceria cell wall biosynthesis

Bacterialcidial, causing bacterial death

over 20ABs

all contain aminosugar structures

e.g. streptomycin, neomycin, kanamycin.

mode of action - inhibit synthesis of proteins by bacteria, leading to bacterial cell death - bactericidal

commonly used in low income countires

distrinct individuals compound

mode of action - inhibits synthesis of proteins, preventing growth - bacteriostatic

no longer a first line drug in any developed nation (except for conjunctivitis) due to increased resistance and worries about saftey.

common “drug of last resort”

consist of carbohydrate linkes to a peptide formed of ASs

e.g. vancomycin, teicoplain

mode of action - inhibit bacteria cell wall biosynthesis - bactericidal -leading to bacterial cell death

restistance evolves rapidly

all contain fused aromatic rings with a carboxylic acid group attached

e.g. ciprofloxacin, levofloxacin, trovafloxacin

mode of action - interfere with bacteria DNA replication and transcription - bactericidal -leading to bacterial cell death

potent ABs commonly used as “drugs of last resort”

all conain 2-oxazolidone somewhere in their strucutre

e.g. linezolid, posizolid, tedizolid, cycloserine

mode of action - inhibit synthesis of proteins by bacteria, preventing growth - bacteriostatic

first commercial ABs were sulfonamides

all contain the sulfonamide group

e.g. prontosil, sulfanilamide, sulfadiazine

mode of action - dont kill bacteria but prevent their growth and multiplication. cause allergic reactions in some patients - bacteriostatic

becoming less popular due to development of resistance

all contain 4 adjacent cyclic hydrpcarbon rings

e.g. tetracycline, doxycycline, limecycline

mode of action - inhibit synthesis pf proteins by bacteria, preventing growth - bacteriostatic

second most prescribded ABs in the NHS

all contain a14-,15-,16-membered macrolide ring

e.g.erythromcycin, clarithromycin

mode of action - inhibit protein synthesis by bacteria, occadionally leading to cell death

can also demonstrate antiviral activity

all contain an aromatic ring bridged by an aliphatic chain

e.g. geldanamycin, rifamycin

mode of action - inhibit the synthesis of RNA by bacteria, leading to cell death - bactericidal

2 groups of ABs that act synergistically

combination of 2 structurally differing compounds from group denoted A & B

e.g. pristinamycin IIA, pristinamycin IA

mode of action - inhibit synthesis of proteins by bacteria, leading to cell death - bactericidal

instances of restistance rare

all contain a lipid bonded to a peptide

e.g. daptomycin, sufactin

mode of action - disrupt multiple cell membrane functions leading to cell death - bactericidal

• inhibit of cell wall synthesis - penicilin, vancomycin (gram +)

• inhibition of DNA-replication or transcription - nitroimidazole

• inhibition of protein synthesis at the ribosome

• inhibition of essential metabolic pathways

• cell membrane - +&-

bacteriostatic - reversibe inhibiton; e.g. tetracycline, macrolide, lincosamides

bactericidal - irreversible killing without cell lysis; e.g. aminoglycosides, rifampicin

bacteriolytic - irreversible kill with cell lysis; e.g. ß-lactams, polymyxine

• broad-spectrum ABs - active against a wide range of disease-causing bacteria (e.g. ß-lactams, tetracycline,macrolides)

• narrow-spectrum ABs - target particular types of bacteria, such as gram- or gram+. CAVE microbiological detection of causative agent and susceptibility testing (e.g. glycopeptides)

pathogen dependent

measurable with different methods:

• minimal inhibition concentration (MIC), minimal in vitro concentration, which inhibits bacterial growth

• minimal bactericidal concentration (MBC) minimal in vitro concentration, which kills all bacteria within 24h

according to ISO:

Susceptible:

• a bacterial strain is said to be S to a given antibiotic when its inhibited in vitro by a concentration of this drug that is associated with a high likelihood of therapeutic success

intermediate:

• the sensitivity of a bacterial strain to a given AB is sait to be I when its inhibited in vitro by concentration of this drug associated with an uncertain therapeutic effect.

Restistant:

• a bacterial strain is said to be R to a given AB when its inhibited in vitro by a concentration of this rug that is associated with a high likelyhood of therapeutic failure

in vitro survival and multiplication of bacteria in presence of therapeutically relevant (in vivo achievable) concentrations of ABs -> pathogen persistence and therapeutic failure

• enzymatic inactivation of compounds

• reduction of intracellular concentration

• alteration/replacement of the cellular target

• non specific mechanism

loss of antimicrobial activity resulting from

• chemical modification of the agent - aminoglycoside modifiyng enzymes

• enzymatic cleavage of the agen - by ß-lactames e.g.

AB concentration is not suffient to kill bacteria of to inhibit bacterial growth mediated by:

• decreased influx via modified or down-regulated porins

• increased efflux via transport systems

porins or outer membrane serve as “entrance” into the bacterial cell

OmpF - tetracycline, chloramphenicol, ß-lactams

OmpC - ß-lactams

antibacterial agents “lose” their target via

• chemical modification of the target

• target modification via point mutations

• target protection

• replacement of the susceptible target

horizontal resistance spread occurs via mobile genetic elements (MGE)

• plasmids

• transposons

• gene cassettes/integrons

which carry resistance genes = horizonatl gene transfer

• extrachromosomal, ds, mostly circular DNS 1,5-100kbp

• autonomous replication - dont need host cell

• multicopy <-> low copy

• one or multiple resistance genes

• ori region for autonomous replication

• mob genes for mobilisation- need more to transfer

• tra-genes for transfer between baczeria - conjugative - give bacti ability to transfer plasmid between bacti

• ds DNA, 4-60kbp

• non-autonomous replication thus integration into chromosome pr plasmid

• one or multiple resistance genes

• eventually conjugative (tra)

• jumping elements - transposition - places are defined

• tnp - region - says where transposon is

• tra-tnp - for conjugation (expression of the apperatus)

• dsDNA, 0.4-1.5kb

• resistance gene + recombination site - contains it

• non-autonomous replication

• no transposition

• integration in one or multiple cassetts in one integron

• integrase mediated site-specific recombination

• aadB - carries recombination site and elements its on is important for replication

• 5’ covered element: integrase intl1

• 3’ consierved element: sulfonamid resistance gene sul1

• transduction

• conjugation/mobilisation

• transformation

• close contact

• resistance genes on MGE’s

• selective pressure

• AB producers: funci or bacteria = selective advantage

• producers must be protected from their own metabolites

• -> mechanism of protection: e.g. efflux systems

• mobilization of resistance genes via MGEs

• horizontal gene transfer into other species

• adaptation via mutation

• acquisition of AB resistance genes by bacteria in response to tge selection pressure of AB use

1. co-selection

2. maintenance and rescue systems (Toxin/antitoxin; Postseggregational killing

3. biological cost & fitness compensation

plasmid maintenance

• rep gene

• toxin/Antitoxin

• Res,ssb

plasmid transfer

• T4SS conjugation

• mob

resistance

• erm (B)

• vanA cluster

• bleomycin

• heavy metall/Cu

“Virulence”

• hyl genomic island

• various pili cluster

• peroxide reductase

• lysozyme

metabolism

• PTS

• ABC porter

• Metall-Homeostasis

• Carbohydr. kinass

• Carbohydr. DC