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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 • • • • • • • 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