Lecture 7: Antimicrobials Mechanisms of Action

Learning Goals

❏ To understand the mechanisms of action of antimicrobial agents

❏ To understand the bases for a rational use of antimicrobials agents
❏ To describe the main groups of antimicrobials
❏ To give some examples of antimicrobial for each particular group
❏ To differentiate the target microorganisms of the most relevant antimicrobial agents

NOSOCOMIAL INFECTIONS: CASE STUDY / RLS

● Bacteria causes 18 deaths in a Hospital in Madrid

● 2 babies died due to hospital bacteria in Barcelona → Klebsiella pneumoniae
● 40% of people infected with Pseudomonas aeruginosa die → multiresistance

ANTIBIOTICS AND CHEMOTHERAPEUTIC AGENTS

● Antibiotics: antimicrobial agents produced by microorganisms that kill or inhibit other

microorganisms
○ e.g: Penicillin, streptomycin, etc
● Chemotherapeutic agents: antimicrobial agents of synthetic origin
○ e.g: Nalidixic acid, isoniazid, etc
● Selective toxicity
○ Ability to suppress/ kill an infecting microbe without injuring the host
○ E.g: therapeutic doses of gentamicin kills bacteria but not toxic to eukaryotic
mammalian cells → impact on healthy gut flora?
● Antibacterial spectrum → range of antimicrobial activity against bacteria
○ BROAD spectrum: drug can inhibit variety of gram + and gram - bacteria
○ NARROW spectrum: drug active against limited variety of bacteria
● Bacteriostatic antibiotic: inhibits the growth of bacteria but does not kill
○ Minimum inhibitory concentration (MIC): lowest antibiotic concentration that
inhibits the growth of the bacteria
● Bactericidal antibiotic: kill the bacteria
○ Minimum bactericidal concentration (MBC): lowest antibiotic concentration that
kills 99.9% of the bacterial population

Meningitis

● Inflammation of the meninges

● Causative agent: bacteria, virus, fungi, parasites (unknown)
● Empirical therapy: Broad spectrum antibiotics (combination), clinical history
● Good sampling: CSF extraction,
● Correct identification of causative agent
● Specific treatment: broad to narrow-spectrum antibiotic (no need for combination)
ANTIBIOTIC: Mechanism, Types, Combination

● Antibiotic combination
○ Broaden the antibacterial spectrum for empirical therapy or the treatment of
polymicrobial infections
○ Prevent the emergence of resistant organism during therapy
○ Achieve a synergistic killing effect
● Antibiotic synergism
○ Combination of 2 antibiotics that together have enhanced bactericidal activity
○ I.e. Penicillin (inhibits cell wall synthesis) + Gentamicin (inhibits protein synthesis)

Antibiotics: Common Mechanisms

1. Prevent cell wall synthesis → many different ways of doing so

a. E.g: penicillin, carbapenems (used for multiresistant bact.), vancomycin
b. Inhibit peptidoglycan synthesis
c. Stops peptidoglycan cross-link
i. Need to bind between subunits: N-acetylglucosamine with
N-acetylmuramic acid
ii. Lysozyme, autolysins, penicillin and cephalosporin stops it’s aggregation
2. Inhibit protein synthesis (e.g: chloramphenicol) → at ribosome
3. Prevent folic acid metabolism
4. Inhibit DNA/RNA synthesis: DNA gyrase, DNA-directed RNA polymerase, RNA
elongation
5. Alter cytoplasmic membrane structure and function (make holes)
Sites of Antibiotic Activity

CELL WALL - PEPTIDOGLYCAN

● Gram Positive Bacteria (PURPLE): thick layers of peptidoglycan

● Gram Negative Bacteria (PINK): thin layer of peptidoglycan, include LPS
● Mechanism of penicillin and penicillin-derivatives
○ Inhibition of bacterial cell wall synthesis → cross linking of peptides