bio 207 lecture 9: antimicrobial therapy and discovery

antibiotic

compounds produced by one species of a microbe that can kill or inhibit growth of other microbes

successful antimicrobial compounds exhibit

selective toxicity and target processes, structural/physiological differences only occuring in target species

bactericidal vs bacteriostatic

kill vs inhibit

Minimal inhibitory concentration

lowest concentration of drug that prevents growth

cell wall antibiotics include penicillin, which is more specifically classified as a

beta-lactam antibiotic

how does penicillin work?

• structure contains condensed amino acids that form a beta-lactam ring structure

• ring chemically resembles peptide crosslink in peptidoglycan

• penicillin can bind to and inhibit transpeptidase enzyme (penicillin-binding proteins) that cross links new peptidoglycan chains

• peptidoglycan becomes less structured and more susceptible to pressure

penicillin is more effective against gram (positive/negative) bacteria because (?)

positive; does not readily pass through gram negative outer membrane

ampicillin

variant of penicillin that more easily penetrates outer membrane and thereby has activity against gram positive and negative bacteria

bacteria develop resistance to penicillin and other beta-lactam antibiotics in two ways

• beta-lactamase enzyme (degrades/cleaves beta-lactam ab before penicillin reaches the cell)

• altered transpeptidase (will not bind to beta-lactam ab)

methicillin resistant s. aureus is an example of antibiotic resistance against methicillin:

• produces nonspecific beta-lactamase binding protein, broad range of resistance

• inhibits most beta-lactams

• arose from mutations that caused transpeptidase to no longer bind beta-lactam ab of methicillin

gramicidin

• pokes holes in cell membrane to kill bacteria and disrupt homeostasis

• inserts into membranes and forms leaky cation channel → disrupts ion concentration gradients

• problem: targets cell membrane which would also apply to eukaryotic cells

antibiotics are considered secondary

metabolites (no apparent primary use in the producing organism)

microbial antibiotic resistance mechanisms can also include

• only finishing synthesis when exported from cell

• making enzymes to disable antibiotics

• drug resistance mechanisms can transfer horizontally to pathogens

• short generation times and large population size selecting for resistance more quickly

three strategies for antibiotic resistance

1. keep/push antibiotics out of cell or destroy them (prevent entry)

2. prevent antibiotics from binding the target

3. dislodge an antibiotic already bound to target (reverse binding)

bacteria can protect themselves against antibiotics and keep them out of the cell by

• destroying antibiotic before it enters

• decrease membrane permeability of outer membrane (ex. narrowing pores in porins)

• pump antibiotic out of cell via specific transporters

multidrug efflux pumps (MDR)

nonspecific and can export many different kinds of antibiotics

bacteria can protect themselves against antibiotics and prevent binding to target by

• modifying target

• adding modifying groups that inactivate the antibiotic and decrease binding ability (increasing MIC)

bacteria can protect themselves against antibiotics and dislodge an antibiotic already bound to its target by

ribosome protection/rescue: gram-positive bacteria can produce proteins binding to ribosomes that dislodge macrolide antibiotics bound near peptidyltransferase site

fungal infections are more (difficult/simple) to treat than bacterial infections

difficult; they are eukaryotes and have many efficient mechanisms that inactivate antibiotics and drugs

fungal infections can be divisded into two main groups

• superficial mycoses: treated topically

• systemic mycoses: treated internally