Alexander Flemming
1928- made penicillin
Antimicrobials
antibioticls/antibacterial-bacteria
antivirals- viruses
antiparasitic agents- parasites
antifungals-fungi
natual antibiotics
produced by living organisms
synthetic antibiotics
created in a lab
semi-synthetic antibiotics
natural antibiotics modified by biochemist
ideal chemotherapeutic agent
1.Does not induce drug allergy in the host/patient
–10% of the population allergic to penicillin
2.Does not induce drug resistance in the target organism/pathogen
–Drug resistance is a major problem in the control of disease with chemotherapeutic agents today.
3.Exhibits a high degree of selective toxicity;
selective toxicity
Exploitation of differences in cell morphology between target and host organisms
Ex. b-lactam antibiotics target cell wall (peptidoglycan synthesis) of a bacterial cell
chemotherapeutic index
selective toxicity;
possesses a high therapeutic ratio as measured by
broad spectrum
less discrimination and targets a wide range of organisms
narrow spectrum
only targets a select group while leaving others unharmed
roles of cell wall synthesis inhibitors
•Major means of bacterial control
•Highly favorable chemotherapeutic indices
•But not without problems
•Hypersensitivity (allergies; CDC figures around 10%)
•Increasing number of resistance mechanisms are constantly evolving in bacteria
CW synthesis inhibitors
1.b-lactams
1a. Penicillins
1b. Cephalosporins
1c. Monobactams
1d. Carbapenems
2.Glycopeptides
3.Polypeptides
4.Acid-fast Drugs
peptidoglycan synthesis
•Complex, multi-step process
•Involves a large number of enzymes, structural membrane proteins, transporters, etc.
•Intracellular and extracellular phases
Transpeptidase (TP)-penicillin binding protein synthesis of cross link
b-lactam antibiotics
mech: competitively bind to transpeptidase and prevent peptidoglycan crosslinking
B-lactams: penicillin
Examples: Penicillin G, Penicillin V
Spectrum: primarily G+ organisms
Additional Information: susceptible to b-lactamase
B-lactamase
which are enzymes that bind to β-lactam antibiotics and destroy them; this and the limited spectrum of penicillin have led to the creation of many semi-synthetic penicillins
B-lactams: Semi-synthetic penicillin
“-cillin”
Methicillin, Oxacillin, Cloxacillin, Dicloxacillin, Nafcillin
Spectrum: primarily G+
Additional Information: increase resistance to b-lactamases
Ampicillin, Amoxicillin, Piperacillin
Spectrum: Broad (G+/G-)
Additional Information: often combined with β-lactamase inhibitor
response to B-lactamase
•Inhibitor binds to β-lactamase permanently, enhancing activity and effectiveness of penicillin
–Augmentin/Clavulin is a combination of amoxacillin (broad spectrum, semi-synthetic penicillin) and clavulanate (β-lactamase inhibitor)
B-lactams: Cephalosporin
Examples start with “Cef-”
or “Ceph-”
Cefotaxime Cephalexin
Ceftriaxone Cephalothin
Cefuroxime Cephamycin
Spectrum of B-lactams: Cephalosporin
Spectrum
1st generation: Primarily gram-positive coverage, some gram negative
2nd generation: Improved gram-negative coverage
3rd and 4th generation: Extended to most gram-negative
5th generation: Treatment for MRSA
Additional Information: more resistant to b-lactamases, less likely to produce allergy than penicillin
B-lactams monobactam
Example: Aztreonma
Spectrum: primarily aerobic G-
Additional Information: resistant to β-lactamase, can be nebulized to treat lung infections
B-lactams carbapenem
Examples: Imipenem, Meropenem
Spectrum: Broad (G+ and G-)
Additional Information: tend to be less susceptible to bacterial resistance mechanisms but can be toxic to host, typically reserved for those with drug-resistant pathogens
glycopeptides
Examples: Vancomycin, Dalbavancin, Oritavancin
Mechanism: binds to the D-Ala-D-Ala moiety of side chain, prevents transpeptidases (TP aka PBP) from creating crosslink and transglycosylases (TG) from creating NAM-NAG polymer synthesis
Spectrum: G+
Additional Information: useful against MRSA, can be more toxic than other cell wall inhibitors
polypeptides: bacitracin
Mechanism: interferes with bactoprenol, which transports peptidoglycan precursors across membrane for external synthesis
Spectrum: G+
Additional Information: common in topical antibiotic creams
acid fast cell wall synthesis inhibitors - ioniazid
interferes with synthesis of mycolic acid
acid fast cell wall synthesis inhibitors- ethambutol
interferes with synthesis of arabinogalactan
acid fast cell wall synthesis inhibitors- Cycloserine
Mechanism: interferes with formation of peptidoglycan sidechain formation
Additional Information: can be useful against G+
cell membrane inhibitors
1.Polypeptides
2.Ionophores
3.Bacteriocins
4.Acid-fast Drugs
Polypeptides: Polymyxins
Examples: Polymyxin B, Polymyxin E (Colistin)
Mechanism: disrupt the membrane and increase permeability, causing cell lysis
Spectrum: G-
Additional Information: Polymyxin B often found in topical antibiotic creams, Polymyxin E is considered a “last-resort” antibiotic for multidrug resistant gram negative bacteria, has increased toxicity to host
pyrazinamide
Mechanism: diffuse into cells and pyrazinamidase converts to pyrazinoic acid, causing destructive physiological changes
Spectrum: Acid Fast
protein synthesis inhibitors
1.Oxazolidinones
2.Aminoglycosides
3.Tetracyclines
4.Macrolides
5.Lincosamides
6.No specific class
Chloramphenicol
Mupirocin
Streptogramin
Ribosome function
polypeptide synthesis
oxazolidinones
Examples: Linezolid, Tedizolid
Mechanism: synthetic peptide that binds to 23S rRNA of 50S subunit and prevents initiation of ribosomal assembly
Spectrum: G+
Additional Information: substitute treatment for drug-resistant S. aureus
aminoglycosides
Examples: Amikacin, Capreomycin, Gentamicin, Kanamycin, Neomycin, Paromomycin, Spiramycin, Streptomycin, Tobramycin
Mechanism: irreversible binding to 30S subunit, blocks translation and causes incorporation of incorrect amino acids into proteins
Spectrum: G-
Additional Information: do contain some renal and CNS side effects, Neosporin typically is Neomycin, Polymyxin B, and Bacitracin
tetracyclines
Examples end in “-cycline: Doxycycline, Minocycline, Tetracycline, Tigecycline
Mechanism: binds to 30S subunit and inhibit tRNA from entering A-site
Spectrum: Broad (G+ and G-) as well as cell wall-less
Additional Information: reduced usage due to wide-spread resistance and liver/renal toxicity among other side effects, though still effective against atypical infections and used to treat severe acne, not recommended for pregnant/nursing or children
macrolides
Examples: Azithromycin, Clarithromycin, Erythromycin, Natamycin, Telithromycin
Mechanism: bind reversibly to 23S rRNA in P-site of the 50S subunit and inhibit both peptidyl transferase and translocation
Spectrum: Broad (G+ and some G-)
Additional Information: topical forms exist, have anti-inflammatory properties and can be used to treat diseases like COPD, some of the most prescribed antibiotics in USA
Lincosamides
Examples: Clindamycin
Mechanism: bind to 23S rRNA of 50S subunit and prevent translocation
Spectrum: G+ and anaerobic G-
Additional Information: increases risk of opportunistic Clostridioides difficile colitis (aka Clostridium difficile or C. diff.)
Chloramphenical
Mechanism: bind to 23S rRNA in 50S subunit and prevents peptidyl transferase
Spectrum: Broad (G+ and G-)
Additional Information: severe side-effects (aplastic anemia, bone marrow suppression, neurological damage, kidney, liver, and GI issues), many drug interactions, used in eye drops but rarely preferred IV/orally over safer drugs
mupirocin
Mechanism: bind to tRNAIle and prevents isoleucine incorporation into polypeptide chain
Spectrum: G+
Additional Information: topical antibiotic, used to treat MRSA
streptogramin
Combination drug (Dalfopristin1 and Quinupristin2)
Mechanism: bind to the 50S subunit and prevent elongation (peptidyl transferase1 and translocation2)
Spectrum: Broad (G+ and G-)
Additional Information: often effective at treating vancomycin resistant organisms, bacteriostatic individually but bactericidal when administered together
nucleic acid synthesis inhibitors
1.Quinolones
2.Nitroimidazoles
3.Acid-fast Drugs
quinolones
Examples: Ciprofloxacin, Levofloxacin, Moxifloxacin, Ofloxacin, Nalidixic Acid
Mechanism: target DNA Gyrase and Topoisomerase IV, prevent DNA replication
Spectrum: Broad (G+ and G-)
Additional Information: many side effects, rarely given to children/elderly/pregnant/nursing
nitroimidazoles
Examples end in “-nidazole”: Benznidazole, Metronidazole, Tinidazole
Mechanism: produce ROS that damage DNA, depletes thiol found in many enzymes/cofactors
Spectrum: Anaerobic bacteria as well as some parasitic infections
acid fast nucleic acid synthesis inhibitors -clofazimine
Mechanism: bind to guanine, prevents replication and transcription
acid fast nucleic acid synthesis inhibitors- rifamycin
Examples: Rifampin, Rifaximin
Mechanism: bind to RNA Polymerase, prevents transcription
Additional Information: can be used to treat other select G+ and G- infections
metabolite inhibitors
1.Antifolates
1a. Sulfonamides
1b. Trimethoprim
Acid-fast Drugs
Antifolates: Sulfonamides
Examples begin with “Sulfa-”: Sulfadiazine, Sulfadoxine, Sulfamethoxazole, Sulfanilamide
Mechanism: competitively inhibit Dihydropteroate Synthetase
Spectrum: Broad (G+ and G-)
Additional Information: Second generation enhance effectiveness of the inhibition and improve pharmacokinetics
antifolates: trimethoprim
Mechanism: competitively inhibits Dihydrofolate Reductase
Spectrum: Broad (G+ and G-)
Additional Information: Sulfonamides and Trimethoprim are often given together as Co-Trimoxazole to prevent resistance via mutation
dapsone
Mechanism: competitively inhibits Dihydropteroate Synthetase
Spectrum: Acid Fast
Additional Information: has anti-inflammatory properties
bedaquiline
Mechanism: blocks ATP Synthase
Spectrum: Acid Fast
Additional Information: used to treat multidrug-resistant tuberculosis (MDR-TB)
MRSA
Methicillin Resistant Staphylococcus aureus
Staphylococcus aureus
•35-40% of the population are carriers for S. aureus
–2-3% are MRSA carriers in general population
–5-6% of hospitalized patients have [or get] MRSA
–
•~1.2 million “Staph” infections in the U.S. annually (~10% become invasive)
–12 million “soft skin/tissue infections”, often undiagnosed
daptomycin (cubicin)
•targets gram-positive cell membrane approved in 2003
–Effective against MRSA
–Potential severe side-effects
–Daptomycin resistant S. aureus was first observed in 2005
•Mutations within the cell membrane render the drug ineffective
ceftaroline (teflaro)
•is a beta-lactam that can inhibit PBP2A found in MRSA, approved in 2010
–Risk for hypersensitivity as well as C. difficile infection
–Resistance detected in 2011 due to mutations in the PBP2A protein
Why does this resistance evolve bacteria?
mutations
DNA transfer and genetic recombination
transformation
transduction
conjugation
plasmid promiscuity
bacteria like to combine beneficial genes from multiple plasmids together
conjugation between bacteria in the same organism
given exposure to antibiotics, gut bacteria can become resistant and pass resistance to infectious bacteria
last resort treatment
polymyxins (colistin)
cause of antibiotic resistance
over-prescribing of antibiotics
patients not finishing their treatment
over-use of antibiotics in livestock and fish farming
poor infection control in hospitals and clinics
lack of hygiene and poor sanitation
lack of new antibiotics being developed
prevent drug resistance
public awareness
sanitation and hygiene
antibiotics in agriculture and the environment
vaccines and alternatives
rapid diagnostic
human capitol