Antibiotics Resistance - 20W

Antibiotic resistance
Resistance
General considerations
 Resistance – ability of the target microorganism to inactivate or

negate harmful effects of the antibiotic which results in the survival
of the target microorganism
 Extends much further back than the antibiotic era

 Mutual competition of the environmental antibiotic producers
 Multiple drug resistance (MDR) indeed complicated the issue as

microorganism becomes resistant to different classes of antibiotics
 Resistance to at least 3 different classes of antibiotics
 Panresistance – resistance to ALL known antibiotics/classes in use

Resistance
R&D
Ventola, 2015
Resistance
Timeline
Ceftazidime – 3rd gen. cephalosporin

Levofloxacin – Q
Linezolid – protein synthesis inhibitor
Daptomycin – cell membrane disruptor
Ceftaroline – cephalosporin
Ventola, 2015
…some major MDR species
 Major Gram (+) MDR organisms:

 MRSA (methicillin-resistant S. aureus)
 VRE (vancomycin-resistant Enterococcus)
 Penicillin-resistant Streptococcus pneumoniae
 Mycobacterium tuberculosis
 Clostridium difficile
 Major Gram (-) MDR organisms:

 Acinetobacter baumannii
 Pseudomonas aeruginosa
 Salmonella spp.
 E. coli
Mechanisms of resistance
Major 4 groups
 Enzymatic inactivation of the drug
 Β-lactamases
 Antibiotic inactivating enzymes in general
 Alteration of the drug target

 Ribosome protection
 Penicillin-binding proteins protection
 Reduced cellular uptake (due to porins)

 Alteration in cell membrane
 Increased efflux of the drug (due to efflux pumps)

 Variety of efflux pumps
 Significantly reduce the effective concentration of the antibiotic in
bacterial cell  no effect
Origins of resistance
 Conjugative plasmids – horizontal gene transfer
 R-factors
 Insertion sequences
 Activation of antibiotic resistance genes
 Transposons
 Mobile genetic elements; travel randomly within the genome
 Recombination of foreign DNA into the chromosome (genomic DNA)
 Mutations in bacterial chromosomes
 Antibiotic resistance genes are very common among soil antibiotic producers
 Play protective role for the antibiotic producing host
R-factors
 Conjugative plasmids that are easily exchanged by the bacterial community,
carrying resistance genes to antibiotics and other antimicrobials
 Usually contain multiple resistance genes (to different classes) under the same
promoter
 RP4 in P. aeruginosa:
 Ampicillin
 Kanamycin
 Tetracycline
 R1 in different Gram (-)
 Ampicillin
 Sulphonamides
 Trimethoprim
 pSH6 in S. aureus:
 Gentamicin
 Trimethoprim
 kanamycin
Efflux pumps
 Protein complexes in the cell membrane in both Gram (-) and Gram (+)
that capture the antibiotic from the cytoplasm/periplasm and export it
outside of the cell
 Reduce the effective concentration of antibiotic
 Have a very wide substrate profile
 Of clinical relevance only when overexpressed

Extracellular
Periplasm
Cytosol
Origins of resistance
 Innate resistance associated with variations in the structure of the

cell envelope resulting in decreased permeability of antibiotics
 Reduced cellular uptake
 Phenotypic results from adaptation to growth and survival within a

specific (antibiotic containing) environment
 Microorganisms lose their resistance upon subculture into

conventional media that contains no antibiotic
Resistance to β-lactams
Enzymatic inactivation of the drug
 Predominantly affects natural antibiotics

 Β-lactams (e.g., penicillins, cephalosporins, carbapenems);
about 1000 β-lactamases (>20 different classes) are currently
known
 Enzymatically cleaves the chemical structure (e.g., β-lactam ring)

that is responsible for the antimicrobial activity of the antibiotic
 Can be encoded on the plasmids or chromosomally
 Occurrence in Gram – is higher than in Gram +

Enzymatic inactivation of the drug
 Antibiotic combination with a β-lactamase inhibitor:

 Clavulanic acid
 No antimicrobial activity by itself!
https://pubchem.ncbi.nlm.nih.gov/compound/Clavulanic-acid
 Augmentin – β-lactam (amoxicillin) + clavulanic acid

 Benefits?
 Metalloenzymes are mostly resistant to β-lactamase inhibitors!
Alteration of PBPs
 PBPs – penicillin-binding proteins (e.g., transpeptidase)

 Bacterial enzymes involved in the late stages of peptidoglycan synthesis
 Modification of PBPs makes these enzymes invulnerable to binding of β-lactam

drugs  no inhibition of cell wall synthesis  no antimicrobial activity
 Occurrence higher in Gram + than in Gram -

Resistance to glycopeptides
 Vancomycin
 Inhibit cell wall synthesis – peptidoglycan assembly
 Bind to the peptidoglycan precursors and NOT the enzymes
 D-serine/D-lac in place of D-alanine – reduction in binding affinity of

glycopeptides
 “Piling up” unlinked peptidoglycan precursors that soak up the
antibiotic
 Resistance emerged due:

 to wide-use of oral glycopeptides to treat C. difficile
 Glycopeptides as feed additives to animals
Hugo and Russell, 2011. Pharmaceutical microbiology)

Resistance to aminoglycosides
Drug modification
 Exert their effect by binding to ribosome and interfering with the protein synthesis
 Enzymatic modification of the drug (aminoglycoside) significantly reduces drug’s

ability to interact with its target
 Achieved by bacterial enzymes:
 Aminoglycoside phosphatases
 Aminoglycoside acetyltransferases
 Aminoglycoside nucleotidyltransferases
Ramirez and Tolmasky, 2010
 Methylation of the ribosome (ribosome protection) is responsible for

aminoglycoside resistance as well
 Exhibited by aminoglycoside producing organisms
 Little clinical relevance
Resistance to tetracyclines
 Block attachment of the amino acid-carrying tRNA to the 30S subunit of the
ribosome
 Prevent the elongation of the growing peptide chain
 Major modes of resistance to tetracyclines:
 Ribosome protection
 Reduced cellular uptake
 Reduced expression of the pores
 Efflux of the drug
Doi and Arakawa,

2007
Resistance to macrolides
 Prevent the elongation of the peptide chain
 Block peptidyltransferase activity
 Act mostly against Gram (+)

 Gram (-) are impermeable to macrolides – reduced cellular uptake
 Modes of resistance in Gram (+):

 Ribosomal protection (methylation)
 Macrolide efflux
 Abundant in S. aureus
 Ribosomal mutation that reduces binding of the macrolides:

 Clinical isolates of S. pneumoniae
Resistance to fluoroquinolones
 Inhibit DNA synthesis
 DNA gyrase and topoisomerase
 Broad spectrum (Gram + and Gram -)
 Major modes of resistance:
 Mutations in gyrase-encoding genes  FQ unable to bind  no antimicrobial

activity
 Reduced drug uptake (in Gram (-) mostly)
 Not an issue for Gram (+)
 Drug efflux
 Only low levels of resistance
 S. aureus, S. pneumoniae, Bacillus sp., M. tuberculosis, E. coli
Resistance to trimethoprim and
sulfonamides
Trimethoprim
Enzymes Enzymes Enzymes

PABA Dihydrofolic Tetrahydrofolic DNA and RNA
acid acid (THF)
 Major modes of resistance:
 Overproduction of DHFR enzyme

 Mutation in DHFR-encoding gene  synthesis of DHFR enzyme that
DOES NOT bind trimethoprim  no antimicrobial activity
Strategies to slow the spread of bacterial resistance
1.Use antibiotics only in cases where necessary

2.Prevent cross-infection among hospital patients
3.Development of new semi-synthetic β-lactams, tetracyclines and
aminoglycosides
4.Development of new antibiotic drug groups
5.Use of drug combination
Major MDRs or MDR candidates
CDC, 2015
 Life-threatening diarrhea
 Commonly hospital-acquired
 Treatable for now but resistance spreads super fast
 400% increase in fatal outcomes between 2000 and 2007
(resistant strains)
 50% of infections in under 65 y/o
 90% of deaths in >65 y/o
CDC, 2015
 Klebsiella and Escherichia spp.

 50% of those who contract bloodstream CRE infections die
 At least 1 type of CRE in every healthcare facilities in 44 states in
USA
CDC, 2015
 Gonorrhea is the 2 most common infection in USA
nd
 UTI and reproductive organs  reproductive complications

Antibiotics Resistance - 20W

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Antibiotic resistance

 Resistance – ability of the target microorganism to inactivate or

 Extends much further back than the antibiotic era

 Multiple drug resistance (MDR) indeed complicated the issue as

 Panresistance – resistance to ALL known antibiotics/classes in use

Ceftazidime – 3rd gen. cephalosporin

 Major Gram (+) MDR organisms:

 Major Gram (-) MDR organisms:

 Alteration of the drug target

 Reduced cellular uptake (due to porins)

 Increased efflux of the drug (due to efflux pumps)

 Recombination of foreign DNA into the chromosome (genomic DNA)

 Mutations in bacterial chromosomes

 Reduce the effective concentration of antibiotic

 Have a very wide substrate profile

 Of clinical relevance only when overexpressed

 Innate resistance associated with variations in the structure of the

 Reduced cellular uptake

 Phenotypic results from adaptation to growth and survival within a

 Microorganisms lose their resistance upon subculture into

 Predominantly affects natural antibiotics

 Enzymatically cleaves the chemical structure (e.g., β-lactam ring)

 Occurrence in Gram – is higher than in Gram +

 Antibiotic combination with a β-lactamase inhibitor:

 Augmentin – β-lactam (amoxicillin) + clavulanic acid

 PBPs – penicillin-binding proteins (e.g., transpeptidase)

 Modification of PBPs makes these enzymes invulnerable to binding of β-lactam

 Occurrence higher in Gram + than in Gram -

 D-serine/D-lac in place of D-alanine – reduction in binding affinity of

 Resistance emerged due:

Hugo and Russell, 2011. Pharmaceutical microbiology)

 Enzymatic modification of the drug (aminoglycoside) significantly reduces drug’s

Ramirez and Tolmasky, 2010

 Methylation of the ribosome (ribosome protection) is responsible for

 Major modes of resistance to tetracyclines:

Doi and Arakawa,

 Act mostly against Gram (+)

 Modes of resistance in Gram (+):

 Ribosomal mutation that reduces binding of the macrolides:

 Major modes of resistance:

 Mutations in gyrase-encoding genes  FQ unable to bind  no antimicrobial

Enzymes Enzymes Enzymes

 Major modes of resistance:

 Overproduction of DHFR enzyme

1.Use antibiotics only in cases where necessary

 Klebsiella and Escherichia spp.

 UTI and reproductive organs  reproductive complications

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