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Hansen’s disease (leprosy)
• Definition: long lasting infection with Mycobacterium leprae causing
disfigurement due to loss of neurological tissue & function and trauma
• Epidemiology: globally about 2 million people are infected with M. leprae (S.America, Africa, SE Asia); 213 cases in the US (2009). Armadillo & humans are
the natural reservoirs.
• Transmission: prolonged contact with Hansen’s disease patients; 95% of the
human population is resistant to M. leprae
• Symptoms & signs: After 2-10 yr incubation, skin discoloration/growth, pain,
numbness/loss of sensation, muscle weakness & paralysis, blindness, stuffy
nose, nose bleeds, foot ulcerations.
• Diagnosis: skin biopsy and staining for AFB; M.l. can only be cultured in
mouse foot pads or armadillos; no lab tests with sufficient sensitivity
available
• Treatment: 6 month-2 years multidrug therapy: dapsone (blocks dihydrofolic
acid synthesis), rifampicin and clofazimine [blocks transcription and prevents
the leprosy reaction: ENL (erythema nodosum leprosum)]
Leprosy spectrum and mechanisms of
pathogenesis
Genes and products involved in the immune
response to M. leprae
Lepromatous
leprosy
Lepromatous leprosy
Borderline and tuberculoid leprosy
Features and disease spectrum of leprosy
TT-Tuberculoid L.; BT-Borderline Tuberculoid L.; BBBorderline Leprosy; BL-Borderline Lepromatous Leprosy; LLLepromatous Leprosy (LTT, Lymphocyte Transformation Test)
Phylogenetic tree for Actinobacteria
based upon sequences for 35 conserved proteins
Tb, Hansen’s disease
Diphtheria
Nocardiosis
Actinomycosis
Actinomycosis
• Definition: Slowly progressing deep tissue abscess lesions caused by mixed
infections with anaerobic actinomyces following mucocutaneous trauma.
• Agents: A. israelii or five other spp. are commensals of the oropharynx and
GI. Actinomyces enter deeper tissue and replicate as mixed infection
(Actinobacillusactinomycetemcomitans, Bacteroides, Eikanella coorodens or
Prevotella) to seed pururlent abscess lesions because they require
anaerobiosis.
• Clinical disease: abscesses in mouth, lungs, GI/GU tracts are designated
cervicofacial, abdominal, and thoracic actinomycosis.
• Pathology: sulfur granules and Gram-positive beads or hyphae like
structures; culture isolation of Actinomyces requires anaerobiosis and 10-15
days
• Treatment: abscess drainage and penicillin G
Gram-positive A. israelii
Sulfur granules
Sulfur granules & actinomycosis
Mineralized mass with calcium phosphate and radiating
filamentous actimomyces
Pathognomonic when recovered from a typical lesion
Other infections associated with granules: mycetoma, botryomycosis
Actinomycosis
Nocardiosis
• Definition: lung or systemic or cutaneous infection with aerobic
Nocardia (N. brasiliensis, N. asteroides or 31 other spp), mostly
(~70%) in immunocompromised individuals, that progresses slowly
and is refractory to conventional antibiotic therapy
• Transmission: Nocardia are commensals of the human oropharynx
and ubiquitous in soil; infection is initiated by trauma and
immunossuppression; about 1,000 cases in the US per year
• Clinical disease: pneumonia - night sweats, fever, chest pain, cough,
X-ray w/ pulmonary infiltrates; meningitis – headache, seizures,
neurological deficits, CT scan to detect lesions; endoacarditis – w/
destruction of heart valves and disseminated lesions; skin lesions –
resembling erysipelas or w/ osteitis as Madura foot/hand
• Diagnosis: tissue biopsy or sample, Gram-positive or acid-fast bacilli;
culture supports definitive diagnosis (hold for weeks)
• Treatment: 6 months trimethoprim/sulfamethoxazol; clinical success
dictates whether other antibiotics may be used: amikacin, imipenem,
meropenem, ceftriaxone, moxifloxacin, minocycline and others.
Nocardiosis
Pulmonary Nocardiosis
Branching, beaded, Grampositive rods
CNS Nocardiosis
Cutaneous Nocardiosis
AFB: decolorized w/ 1%
sulfuric acid (Kinyoun)
Madura Foot
Antibiotics, the best drugs against bacterial
infections, are made by microbes
Microbes at war - bacterial
growth inhibition by antibiotics
Purified antibiotics, placed on filter
discs, inhibit bacterial growth
Clinical use of antibiotics selects for
antibiotic-resistant bacteria
Structural and functional diversity in
antimicrobials
Antibiotics are precious
the US consumes 51 tons of antibiotics each day
• Antibiotics permit therapy of human infectious diseases
without establishing diagnosis for the causative agent
• Antibiotics prevent surgical infections and treat hospitalacquired infections
• Antibiotics prolong human life (2-10 yr/person)
• The discovery and licensure of new antibiotics has slowed
to a trickle; there is a need to deeply probe microbial
ecology for producers of antibiotics
• Antibiotics should not be wasted on trivial issues, e.g.
growth enhancement of farm animals (80% consumption
is for live-stock!
Classes of antibiotics and representative members
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β-lactam: penicillin G
Cephalosporin: ceftriaxone
Monobactam: aztreonam
Clavam: clavulanic acid
Carbapenem: imipenem
Glycopeptide: vancomycin
Aminoglycoside:
gentamicin, amikacin,
kanamycin, tobramycin
• Lipopeptide: daptomycin
• Lincosamide: clindamycin
• Macrolide: erythromycin,
azithromycin
• Tetracycline: doxycycline
• Fluoroquinolone:
ciprofloxacin, levofloxacin
• Sulfonamide:
sulfamethoxazole
• Streptogramin:
Pristinamycin
• Oxazolidinones: Linezolid
Antibiotics, their targets and resistance mechanisms
Antibiotic classes
Target
Mode of action
Resistance
β-lactams
Penicillin binding
proteins (PBPs)
Transpeptidation
inhibitor
β-lactamases,
mutant PBPs
Glycopeptides
Lipid II precursor
Blocking cell wall
synthesis substrate
Variant lipid II
Cell wall
Translation (Protein synthesis)
Macrolides
Ribosome
Translation inhibition
Target modification
Tetracyclines
Ribosome
Translation inhibition
Drug efflux
Aminoglycosides
Ribosome
Translation inhibition
Drug modification
Oxazolidinones
Ribosome
Translation inhibition
Target modification
Streptogramins
Ribosome
Translation inhibition
Target modification
Transcription (mRNA synthesis)
Rifamycins
RNA polymerase
Transcription inhibition Target modification
Topoisomerase
Inhibits DNA
replication
DNA synthesis
Fluoroquinolones
Target modification
Antibiotic resistance, a summary
Bacterial cell wall synthesis as a target for
antimicrobial therapy
Cell wall structure of bacteria: common
elements and diversity in crossbridges
Cell wall synthesis in staphylococci
Transglycosylation and transpeptidation
reactions of cell wall synthesis
β-lactam antibiotics inhibit the
transpeptidation reaction
The five main classes of β-lactam antibiotics
Structure
Class
Example
Source
Penicillin
Penicillin G
Penicillium chrysogenum
Cephalosporin Cephalosporin C Acremonium chrysgenum
Monobactam
Nocardicin A
Nocardia uniformis
Clavam
Clavulanic acid
Streptomyces clavulgerius
Carbapenem
Car
Erwinia caratovora
Glycopeptide antibiotics (vancomycin) inhibit
transpeptidation and transglycosylation
Vancomycin resistance
synthesis of an altered cell wall precursor (lipid II)
VanA type glycopeptide resistance
Induction of VanA type resistance
Induction of penicillin and methicillin
resistance in staphylococci
Peptidoglycan recycling and AmpC induction
Regulation of ampC Induction
Folate biosynthesis and its inhibition
PABA and sulfanilamide
Trimethoprim
Bacterial protein synthesis
MLS antibiotics block the ribosomal exit
tunnel
Peptidyl transferase catalytic loop of 23S RNA mutations affecting MLS resistance
Macrolides at the peptidyl-transferase center (PTC)
mutations that change amino acids confer macrolide resistance
Antibiotics that bind to the PCT A site
target for chloramphenicol (CAT), clindamycin (Cli) and
streptogramin (Syn=Synercid) cannot be mutated for resistance
Intrinsic antibiotic resistance of bacteria
vancomycin cannot diffuse across the Gram-negative outer membrane
Tripartite efflux pumps accept substrates in
multiple locations and provide broad spectrum
antibiotic resistance
Structure of bacterial tripartite antibiotic
efflux pumps
Antibiotic resistance by mutation of the drug target
rapid generation and selection for resistant variants
Fluoroquinolones
inhibit bacterial topoisomerase and gyrase to
block DNA replication
Antibiotic resistance by drug modification
slow acquisition of genetic traits and selection for resistance
Aminoglycoside-modifying enzymes
Countering antibiotic resistance
Antibiotic consumers & antibiotic resistance
Global consumption of 73,620,748,816 units (doses) of antibiotics
in 2010 provides for the selection of resistant strains
Antibiotic use affects the human microbiota
Depending on antibiotic used, microbiota are diminished and
then either restored or remain perturbed
Enterococcus faecalis, the professional
among drug-resistant bacteria