MECHANISMS OF ANTIBIOTIC

RESISTANCE

NAME : SUMAN DAS

REG. NO : 17mslsmm20
CENTRE : HUMAN GENETICS & MOLECULAR
MEDICINE
CENTRAL UNIVERSITY OF PUNJAB
 INTRODUCTION
 Antibiotics or antibacterials are a type of antimicrobial used in
the treatment and prevention of bacterial infection. They may
either kill or inhibit the growth of bacteria.
 The conc. of drug at the site of infection must inhibit the
organism and also remain below the level that is toxic to human
cells.
 Antibiotic resistance is defined as microorganisms that are not
inhibited by usually achievable systemic conc. of an
antimicrobial agent with normal dosage schedule fall in the
MIC range.
MECHANISM OF ANBIOTIC ACTION

Fig 1: Different mechanisms of antibiotic action

MECHANISM OF ANTIBIOTIC RESISTANCE

Intrinsic Acquired

Genetic Methods

Chromosomal Methods Extrachromosomal Method

 INTRINSIC RESISTANCE
 It is natural.
 Interaction of many organisms with their environment.
 Resistance of Mycoplasma species to B-lactams
antibiotics, due to lack of cell wall.

Fig 2: Intrinsic resistance

 MUTATIONAL RESISTANCE
Mutations resulting in antimicrobial resistance alter the antibiotic
action via :

I. Modifications of the antimicrobial target.

II. A decrease in the drug uptake.

III. Activation of efflux mechanisms to extrude the harmful

molecule.

IV. Global changes in important metabolic pathways via modulation

of regulatory networks.
 EXTRACHROMOSOMAL METHOD
Extrachromosomal method means acquisition of foreign DNA
coding for resistance determinants through horizontal gene transfer.

Fig 3: Three main strategies of acquisition of external genetic

material by bacteria.
 MECHANISTIC BASIS OF ANTIMICROBIAL
RESISTANCE

1. Modification of the antimicrobial molecule.

2. Prevention to reach the antibiotic target (by decreasing

penetration or actively extruding the antimicrobial compound)

3. Changes and/or bypass of target sites.

4. Resistance due to global cell adaptive processes.

 MODIFICATIONS OF THE ANTIBIOTIC
MOLECULE
I. Chemical alterations of the antibiotic : Production of
enzymes capable of introducing chemical changes to the
antimicrobial molecule.

Different types of reactions catalyzed by modifying enzymes are :

 Acetylation (aminoglycosides, chloramphenicol)

 Phosphorylation (aminoglycosides, chloramphenicol)

 Adenylation (aminoglycosides, lincosamides)

II. Destruction of the Antibiotic Molecule : The main
mechanism of B-lactam resistance relies on the destruction of this
compounds by the action of B-lactamases. This enzymes destroy the
amide bond of the B-lactam ring.

Fig 4: Inactivation of penicillin by penicillinase enzyme

 DECREASED ANTIBIOTIC PENETRATION
AND EFFLUX
I. Decreased Permeability :

Fig 5: Decrease permeability of porin channels

II. Efflux Pumps :There are 5 major families of efflux pumps
including :
a) The major facilitator superfamily (MFS)
b) The small multidrug resistance family (SMR)
c) The resistance nodulation cell division family (RND)
d) The ATP binding cassette family (ABC)
e) The multidrug and toxic compound extrusion family (MATE)

Fig 6: Different types of efflux pumps

 CHANGES IN TARGET SITES
Bacteria have evolved different tactics including i) protection of
the target (avoiding the antibiotic to reach its binding site) and
ii) modification of the target site that result in decrease affinity for
the antibiotic molecule.

Fig 7: Mechanism of target site protection and modification.

 RESISTANCE DUE TO GLOBAL CELL
ADAPTATIONS
Development of resistance to daptomycin (DAP) and vancomycin
are the most clinically relevant examples of resistant phenotypes
that are the result of a global cell adaptive response to the
antibacterial attack.
i. DAP is a lipopeptide antibiotic produced by the innate immune
system.
ii. It exerts its effect by altering cell envelope homeostasis.
iii. It complexed with calcium and directed to the CM.
iv. It oligomerizes at the outer leaflet of the CM and the oligomers
reach the inner CM leaflet.
v. They organize and form transmembrane pore like structure and
promote leakage of ions from the cytoplasm.
Bacteria developed DAP resistance by changing in a three
component regulatory system designated LiaFSR.

LiaFSR is composed of three proteins

a. LiaF, is a transmembrane protein that appears to negatively

regulate the system.

b. LiaS, is a classical sensor histidine kinase protein that

phosphorylates the response regulator.

c. LiaR, is the response regulator of the system.

 REFERENCES
 Munita J. M., & Arias, C. A. (2016). Mechanisms of Antibiotic
Resistance. Microbiology spectrum, 4(2).

 Thomas, C. M., & Nielsen, K. M. (2005). Mechanisms of, and

barriers to, horizontal gene transfer between bacteria. Nature
reviews microbiology, 3(9), 711-721.

 Wilson, D. N. (2013). Ribosome-targeting antibiotics and

mechanisms of bacterial resistance. Nature Reviews
Microbiology, 12(1), nrmicro3155.