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Antibiotic Poster
Antibiotic Poster
Jay Kaplan
CBE/MOL 411
*Content in blue text is novel information not presented in class.
Production Method
Streptomycin is produced by fermentation of S. griseus. Spores are transferred to an
Chemical Diversity
inoculum medium and when sufficient growth is maintained they are moved to a The aminoglycoside class all consist of an amino group bond to a glycoside:
fermentation tank for aquatic subculture production. • Streptomycin 1944 (Streptomyces griseus)
• Neomycin 1949 (Streptomyces fradiae)
• Kanamycin 1957 (Streptomyces kanamyceticus)
• Gentamycin 1963 (Micromonospora)
• Tobramycin 1967 (Streptomyces tenebrarius) Tolerance
• Amikacin 1972 (Semi-synthetic form of Kanamycin) Tolerant populations can outlive exposure to raised antibiotic concentrations without
• Plazomicin 2009 (Semi-synthetic form of Sisomicin) modification of the MIC by slowing down essential bacterial processes.
• This enables prolonged survival under antibiotic exposure. The addition of metabolites
Side Effects: have been shown to re-sensitize aminoglycoside tolerant mutants.
Structure & Synthesis The aminoglycosides have varying degrees of toxicity resulting in ototoxicity, Factors that Impair Aminoglycoside Activity by introducing Tolerance:
nephrotoxicity, and neuropathy. The peripheral neuropathy, encephalopathy, and The absence of metabolites causes the cell to enter a non-growing phase. As such, the cell
Aminoglycosides consist of an amino sugars connected via glycosidic links. neuromuscular blockades are caused by inhibition of quantal release of slows translation which reduces the uptake of aminoglycosides which leads tolerance.
Streptomycin is a trisaccharide of a streptidine, a streptose, and an N-methyl-glucosamine. acetylcholine in the neuromuscular junction pre-synaptically and a post-junctional • Low extracellular pH increases membrane potential which reduces aminoglycoside
binding of of aminoglycosides to the acetylcholine receptor complex. uptake into the cell.
Amikacin in-Depth • Anaerobic conditions result in a very low membrane potential which prevents uptake of
• Developed by Bristol-Banyu Research in 1972. aminoglycosides and essentially makes anaerobic bacteria immune to their action.
• The first semi-synthetic derivative of the Aminoglycosides. • Certain types of translational initiation such as chloramphenicol which blocks peptide
• Kanamycin was acylated at the C-1 amino group of the deoxystreptamine group chain elongation.
with L-(-)-!-amino-"-hydroxybutyric acid. Re-sensitization of Tolerant Cells:
This modification prevents degradation by bacterial resistance enzymes and • Membrane targeting agents such as Rhamnolipids which enable PMF-independent
cellular uptake of aminoglycosides and cell killing.
reduces cross-resistance between Amikacin and other aminoglycosides. However,
• A study found the addition of silver nitrate was found to reduce the MIC of
there has been a rise in resistance with the primary mechanism being acetylation of aminoglycosides by over ten-fold and was PMF-independent.
the 6’-N position by the AAC(6’)-I enzymes.
• Recent research has found numerous compounds capable of inhibiting this class
of enzymes that could be used in conjunction with aminoglycosides. The three
References
CBE/MOL411 Lecture Slides 2022 by M.P. Brynildsen
most promising small molecules are found below: Bryan, L. E., & Kwan, S. (1983). Antimicrobial Agents and Chemotherapy, 23(6), 835–845.
Biosynthetic Gene Cluster: BARKER, E. P. Et al., (1992). Journal of General Microbiology, 138(3), 551–561.
• The BGC is activated by a cascade initiated by slowing cell growth which increases Ezraty, B. Et al., (2017). Molecular Microbiology, 105(1), 115–126.
production of factor A causing accumulation of factor A. Häussler, S. et al., (2020). Antimicrobial Agents and Chemotherapy, 65(1).
• A Factor binds to ArpA dimer enabling RNA Polymerase to initiate transcription of the Ramakrishnan, V. Et al., (2000). Nature, 407(6802), 340–348.
Tolmasky, M. Et al., (2017). Molecules, 22(12), 2267.
adpA gene. This transcriptional promoter along with StrR is the pathway-specific
Wiela-Hojeńska, A. Et al., (2021). Molecules, 26(24), 7456.
transcriptional activator for the whole gene cluster (BGC). Wright, G. E. Et al., (1974). Antimicrobial Agents and Chemotherapy, 5(2), 143–152.