Overview about Aminoglycosides, its classification and others related important information.

1. AMINOGLYCOSIDES
DR. EMILIANO Z. SISON JR.
RPh, ClinPharm, MSPharm, MATCC, PhDEL, PhDPh

2. DRUGS UNDER AMINOGLYCOSIDES
STREPTOMYCIN GENTAMICIN KANAMYCIN
TOBRAMYCIN AMIKACIN SISOMICIN
NETILMICIN PAROMOMYCIN NEOMYCIN
FRAMYCETIN OTHERS

3. Aminoglycosides
All aminoglycosides are produced
by soil actinomycetes.
Obtained from the
species of
Streptomyces
(suffix mycin)
and
Micromonospora
(suffix micin)
Semisynthetic derivatives also end
up with suffix micin.

11. Aminoglycosides
• Bactericidal antibiotics
• Rapidly bactericidal
• Bacterial killing - concentration
dependent (higher the
concentration greater the rate
at which bacteria are killed)

14. General Character of Aminoglycosides Group
 Formulations are Sulfate or hydrochloric salts
 Formulations are water soluble and stable
 Highly polar basic drugs.
 Ionize during dissolution
 Distribution inside the cells is minimal
 Penetration through BBB is minimal
 Least metabolized by hepatic enzymes
 Excretion is mainly renal (unchanged form, through
glomerular filtration)
(Not absorbed from GIT)

15. SPECTRUM OF ACTIVITY
• Narrow spectrum
– Aerobic gram-negative bacilli
– Not effective against
• gram positive cocci & bacilli
• gram negative cocci
• and anaerobes

16. SPECTRUM OF ACTIVITY
• Aminoglycosides are active against various Gram-positive and Gram-negative
organisms.
• Aminoglycosides are particularly potent against members of the Enterobacteriaceae
family, including Escherichia coli, Klebsiella pneumoniae and K. oxytoca,
Enterobacter cloacae and E. aerogenes, Providencia spp., Proteus spp., Morganella
spp., and Serratia spp.
• Furthermore, aminoglycosides are active against Yersinia pestis (Heine 2015) and
Francisella tularensis, the causative agents of plague and tularemia, respectively.
• The class also has good activity against Staphylococcus aureus, including methicillin-
resistant and vancomycin-intermediate and -resistant isolates, P. aeruginosa and to
a lesser extent Acinetobacter baumannii.
• Many Mycobacterium spp. are also susceptible to aminoglycosides including
Mycobacterium tuberculosis, M. fortuitum, M. chelonae, and M. avium.

17. Structures of representative aminoglycosides, including the atypical aminoglycosides
streptomycin and apramycin, 4,6-substituted AGs tobramycin, gentamcin, and amikacin, and the
4,5-substituted AG neomycin.
Kevin M. Krause et al. Cold Spring Harb Perspect Med
2016;6:a027029
©2016 by Cold Spring Harbor Laboratory Press

18. ADVERSE EFFECTS/
TOXICITY
Ototoxicity
Nephrotoxicity
Neuromuscular
blockade

20. AMINOGLYCOSIDES

21. BACTERIAL TARGETS,
MECHANISM OF ACTION AND
SIDE EFFECTS

23. AMINOGLYCOSIDES
RESISTANCE

24. MECHANISMS OF AMINOGLYCOSIDE RESISTANCE
• Aminoglycoside resistance takes many different forms including enzymatic
modification, target site modification via an enzyme or chromosomal mutation, and
efflux.
• Each of these mechanisms has varying effects on different members of the class and
often multiple mechanisms are involved in any given resistant isolate.
• Resistance to aminoglycosides via target site mutations has not been observed
because nearly all prokaryotes, except for Mycobacterium spp. and Borrelia spp.,
encode multiple copies of rRNA.
• Although contemporary large-scale surveillance programs provide an understanding
of phenotypic aminoglycoside resistance among important pathogens, these studies
have generally not focused on the epidemiology of specific resistance mechanisms.

25. Three principal mechanisms for the development of
resistance:
Synthesis of plasmid mediated bacterial transferase enzymes that can inactivate
aminoglycosides.
Mutation/deletion of porin channels resulting in decreased transport of
aminoglycoside into the bacterial cytosol.
By deletion or alteration of the receptor protein on 30S (Target) ribosomal unit
because of mutations. Attachment of drug with 30S ribosomal unit is thus
prevented.

26. ENZYMATIC DRUG MODIFICATION
• Aminoglycoside Modifying Enzymes (AMEs) are often found on plasmids containing
multiple resistance elements, including other AMEs or β-lactamases.
• The mobility of these enzymes might be tied to their origins, which has been
hypothesized to be via horizontal gene transfer from the actinomycetes responsible
for the natural production of aminoglycosides.
• More than 100 AMEs have been described and are broadly categorized into three
groups based on their ability to acetylate, phosphorylate, or adenylate amino or
hydroxyl groups found at various positions around the aminoglycoside core scaffold.
• These modifications decrease the binding affinity of the drug for its target and lead
to a loss in antibacterial potency.
• These three families of AMEs include aminoglycoside N-acetyltransferases
(abbreviated AACs), aminoglycoside O-nucleotidyltransferases (ANTs), and
aminoglycoside O-phosphotransferases (APHs).

27. Sites of chemical modification by representative aminoglycoside-modifying enzymes (AMEs) on
kanamycin A.
Kevin M. Krause et al. Cold Spring Harb Perspect Med
2016;6:a027029
©2016 by Cold Spring Harbor Laboratory Press

28. Examples of aminoglycoside modification by AMEs. (A) An example of chemical modification of
gentamicin catalyzed by the aminoglycoside acetyltransferase AAC(3).
Kevin M. Krause et al. Cold Spring Harb Perspect Med
2016;6:a027029
©2016 by Cold Spring Harbor Laboratory Press

30. OVERVIEW OF STRATEGIES TO
OVERCOME RESISTANCE TO
AMINOGLYCOSIDES MODIFYING
ENZYMES (AMEs)