Cell Membrane Acting Antibiotics

1. Antibacterials affecting Cell Membrane
Dr Ravi Kant Agrawal, MVSc, PhD
Senior Scientist (Veterinary Microbiology)
Food Microbiology Laboratory
Division of Livestock Products Technology
ICAR-Indian Veterinary Research Institute
Izatnagar 243122 (UP) India

2. ANTIBIOTICS AFFECTING CELL MEMBRANES
• Polymyxins
• Daptomycin
• Isoniazid
• Ethambutol

3. Bacterial Cytoplasmic Membranes
• Biologic membranes are composed basically of lipid, protein,
and lipoprotein.
• The cytoplasmic membrane acts as a diffusion barrier for
water, ions, nutrients, and transport systems.
• Most workers now believe that membranes are a lipid matrix
with globular proteins randomly distributed to penetrate
through the lipid bilayer.
• A number of antimicrobial agents can cause disorganization of
the membrane.
• These agents can be divided into cationic, anionic, and neutral
agents.
• The best-known compounds are polymyxin B and
colistemethate (polymyxin E).

4. Polymyxins
• Polypeptide antibiotics
• Generic name used for group of six strongly basic cyclic
compunds A, B, C, D, E & M
• Polymyxin B and Polymyxin E are used therapeutically
• Polymyxin B is a strong bactericidal polypeptide antibiotic
obtained from Bacillus polymyxa
• Used only for topical application or oral administration as
parentral administration leads to toxicity
• Used only as a last resort if modern antibiotics are ineffective or
are contraindicated.
• Typical uses are for infections caused by strains of multidrug-
resistant Pseudomonas aeruginosa or carbapenemase-
producing Enterobacteriaceae.

5. MOA
• Surface active amphipathic agents.
• Rapidly acting bactericidal agent with detergent like action on
cell membrane
• These high-molecular-weight octapeptides inhibit Gram-
negative bacteria that have negatively charged lipids at the
surface.
• Positively charged cyclic peptide interacts with negatively
charged cell membrane: Interact strongly with phospholipids
and disrupt the structure of cell membranes.
• Activity depends on content of phospholipid of cell membrane
complex hence it is not susceptible to G +ve
• Since the activity of the polymyxins is antagonized by Mg2+
and
Ca2+
, they probably competitively displace Mg2+
or Ca2+
from the
negatively charged phosphate groups on membrane lipids.
• Basically, polymyxins disorganize membrane permeability,
causing disruption of membrane so that nucleic acids and
cations leak out and the cell dies.
• Can also inactivate LPS of G- ve by binding to anionic lipid
• The polymyxins are of VIRTUALLY NO USE AS SYSTEMIC
AGENTS since they bind to various ligands in body tissues and
are potent toxins for the kidney and nervous system.

6. Uses
• Used topically to treat G -ve infection of skin, eye and ear.
• Used for Bovine mastitis caused by P. aeruginosa, Klebsiella
spp.
• Polymyxin antibiotics are relatively neurotoxic
and nephrotoxic and may cause allergic reactions
• Resistance: Very few resistant strains have been found.
Polymyxin E
• Polymyxin E (Colistin) by Bacillus colistinus
• Both oral and parentral formulation available
• Almost similar action to polymyxin B but more potent to
Pseudomonas, Salmonella, Shigella.

7. Daptomycin
 Daptomycin is called a Novel cyclic lipopeptide antibiotic
 Similar to that of vancomycin
 Approved for use in 2003
 Lipid portion inserts into the bacterial cytoplasmic membrane
where it forms an ion-conducting channel.
 Marketed under the trade name Cubicin

8. Proposed mechanism of action of daptomycin Daptomycin first binds to the cytoplasmic membrane (step 1)
and then forms complexes in a calcium-dependent manner (steps
2 and 3).
 Complex formation causes a rapid loss of cellular potassium,
possibly by pore formation and membrane depolarization.
 This is followed by arrest of DNA, RNA, and protein synthesis
resulting in cell death. Cell lysis does not occur.

9. Uses of Daptomycin
 Daptomycin is active against many aerobic Gram-positive
bacteria
 Includes activity against MRSA, penicillin-resistant
Streptococcus pneumoniae, and some vancomycin-resistant
Enterococci (VRE)
 Daptomycin is not active against Gram negative strains, since it
cannot penetrate the outer membrane.
 Primarily been used to treat skin and soft tissue infections
 Poor activity in the lung.

10. Isoniazid
 Effective against M. tuberculosis
 Inhibits mycolic acid synthesis
 Targets cell wall fatty acid synthesis
 Only for MTB (not used for other mycobacteria)
 Requires activation by MTB catalase-peroxidase
 Used alone in treatment of PPD-positive persons with latent TB
(i.e., no active disease)
 Resistance show by MTB that have lost catalase gene
 Resistance show by MTB with altered INH targets
 Liver toxicity increases with age
 Hepatitis: Age related. Not given to patient over 35 years old
for prophylactic purpose.
 Other toxicities include peripheral neuropathy (often reversible
by vitamin B6), lupus-like syndrome (~1% of persons though 20%
develop anti-DNA)
 Peripheral neuritis if pyridoxine (Vit.B6) is not given
concomitantly.

11. Ethambutol
 Inhibits MA incorporation to cell wall
 Inhibits cell wall arabinogalactan formation
 No liver toxicity
 Significant toxicities include retrobulbar neuritis affecting
visual acuity and severe skin reactions
 Optical neuritis: inability to distinguish red- green color; optical
acuity test must be given before and during therapy.

12. Thanks
Acknowledgement: All the material/presentations available online on the
subject are duly acknowledged.
Disclaimer: The author bear no responsibility with regard to the source
and authenticity of the content.