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Home , Teixobactin

PharmDr. Hana Kiňová Sepová, PhD. Department of Cell and Molecular Biology of Drugs Faculty of Pharmacy UK History

• Paul Ehrlich (1910, Salvarsan)

• Alexander Fleming (1928, )

• Gerhard Domagk (1932, Prontosil) Geographical distribution of the consumption of Antibacterials for systemic use (ATC group J01) in the community (primary care sector) in Europe, reporting year

ECDC, 2019 2018 use in 2015

http://resistancemap.cddep.org/AntibioticUse.php Consumption of antibacterial drugs for systemic use (J01) in Iran during 2000-2009

Abdollahiasl et al., 2011 950 participants practices about antibiotic consumption in Iran If yes, how many times in recent year? Why do you do it arbitrarily? Because; 1 time 23.2 It is cost benefits 51.0 2 times 31.1 It is accessible 63.2 3 times 28.5 It is easy 56.5 More than 3 16.9 Any trust on doctors 43.6 Have you ever changed the dose of Do you understand the antibiotics’ antibiotics arbitrarily? instructions? Yes 60.1 Yes 48.8 No 39.8 No 51.2 If yes, why did you change? Do you read the instructions before use? To get better soon 62.6 Yes, always 13.0 To decrease the side effects 34.5 Yes, seldom 18.7 I did not have enough 32.0 Never 68.2 In what case/s do you have it arbitrarily? How do you measure the dose of antibiotics? Runny nose 69.9 Base on the instruction 15.3 Coughing 57.9 Doctor’s consultation 13.0 Sore throat 80.3 Pharmacy’s advices 21.6 Fever 63.2 Friends’ advices 29.4 Headache 18.7 On internet 18.7 Vomiting 13.0 Previous orders 51.0 Diarrhea 21.8 Skin rashes 31.9 What are your criteria for antibiotic selection? If yes, why did you change? 31.9 Friends’ advices Was not effective 35.5 36.3 Pharmacy’s advices Was finished 27.6 44.0 Family’s advices Was expensive 26.2 60.3 Previous experiences Had adverse effects 10.5 63.2 Previous prescription Have you ever change the type of antibiotics From where do you take your antibiotics? arbitrarily? Pharmacy 47.4 Yes 53.8 Previous residues 70.5 No 46.1 Hosseinzadeh & Azimian, 2017 World Health Organization (Surveillance of Antibiotic Consumption, November 2018): Iran’s antibiotics consumption was the second highest among 65 countries. Definition

• Prophylaxis and therapy of infectious diseases

• Antibiotics vs. chemotherapeutics

• Biosynthetic, semisynthetic, synthetic Antibiotics

• Three interacing sites: ◦ Macroorganism ◦ Microorganism ◦ Drug Chemotherapeutic index

„The dose makes the poison.“ Paracelsus

dose toxic for host • TI = ▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬ dose effective on microorganism

• The TI, the more effective drug Efficacy of antibiotics

• Bactericidal

(efficacy dependent on time vs. on dose)

vs.

• Bacteriostatic Efficacy of antibiotics

http://www.antimicrobe.org/h04c.files/history/PK-PD%20Quint.asp Efficacy of antibiotics

MIC = minimal inhibitory concentration

MBC = minimal bactericidal concentration Efficacy of antibiotics

• Spectrum of activity:

◦ Narrow (antituberculotics, spectinomycin)

◦ Medium (penicillin, , I. generation , )

◦ Broad (tetracyclins, chloramphenicol, rifampicin, cotrimoxazol, cephalosporins and chinolones of newer generations) Application forms

• Systemic: p.o., parenteral (i.v., i.m.)

• Local: skin, vagina, ear, eye, oral cavity, nasal mucosa Rational antibiotic therapy

• Infectious disease • Source of disease treatable with antibiotics • Sampling • Empirical therapy • Clinical effect • Doses and intervals • • Seriousness of infection • Patient actual condition • Combination of antibiotics • Sequence therapy • De-escalation therapy Mechanism of action

• Inhibition of synthesis • Inhibition of nucleic acid synthesis • Damage of cell membrane • Inhibition of proteosynthesis • Antimetabolites Mechanism of action

• Inhibition of cell wall synthesis • Inhibition of nucleic acid synthesis • Damage of cell membrane • Inhibition of proteosynthesis • Antimetabolites Inhibition of cell wall synthesis Mechanism of action Inhibition of cell wall synthesis Mechanism of action

ß-lactams – binding and inhibition of peptidases, that bridge molecules of Inhibition of cell wall synthesis Mechanism of action

• – inhibition of peptidoglycan units formation

• Vancomycin – inhibition of peptidoglycan net prolongation Mechanism of action

• Inhibition of cell wall synthesis • Inhibition of nucleic acid synthesis • Damage of cell membrane • Inhibition of proteosynthesis • Antimetabolites Inhibition of nucleic acid synthesis Mechanism of action

• Inhibition of DNA-gyrase (topoisomerase)- quinolones • Inhibition of mRNA synthesis - ansamycines • Destruction of bacterial DNA - nitroimidasoles • Inhibition of DNA synthesis in yeasts • Inhibition of DNA synthesis dermatophytes Inhibition of nucleic acid synthesis Mechanism of action Mechanism of action

• Inhibition of cell wall synthesis • Inhibition of nucleic acid synthesis • Damage of cell membrane • Inhibition of proteosynthesis • Antimetabolites Damage of cell membrane Mechanism of action

• Interaction with phospholipides in membrane

• Polypeptide antibiotics Mechanism of action

• Inhibition of cell wall synthesis • Inhibition of nucleic acid synthesis • Damage of cell membrane • Inhibition of proteosynthesis • Antimetabolites Inhibition of proteosynthesis Mechanism of action Mechanism of action

• Inhibition of cell wall synthesis • Inhibition of nucleic acid synthesis • Damage of cell membrane • Inhibition of proteosynthesis • Antimetabolites Antimetabolites Mechanism of action Antimetabolites Mechanism of action Side effects

• 5% of users

• Organ toxicity

• Allergic response

• Suppression and alteration of physiological microbiota Side effects Organ toxicity

• Nephrotoxicity → sulfonamides

• Haematotoxicity → chloramphenicol

• Neurotoxicity → aminoglycosides

• Damage of teeth and bones → tetracyclines Side effects Allergic response

• Drug = antigen → allergic reaction • Penicillin

• Sulfonamides Side effects Suppression and alteration of physiological microbiota

• Lactobacillus spp.

• Candida albicans

• Clostridium difficile Classification of antibiotics and chemotherapeutics o ß-lactam antibiotics:o Glycopeptide • antibiotics • Cephalosporins o Ansamycines • Other ß-lactams o Sulfonamides and o Tetracyclines pyrimidines o Aminoglycosides o Nitroimidasoles and nitrofuranes o Macrolides o Quinolones o Lincosamides o Other o Amphenicols chemotherapeutics o Polypeptide o Local antibiotics antibiotics o New antibiotics Classification of antibiotics ß-lactam antibiotics

• Time-dependent agents

• ß-lactam circle

• Penicillins (6-aminopenicillanic acid)

• Cephalosporins (7-aminocephalosporanic acid)

• Other ß-lactams Classification of antibiotics ß-lactam antibiotics – mechanism of action • Inhibition of Penicillin- Binding • Resistance due to the in PBPs gene • Bactericidal activity Classification of antibiotics ß-lactam antibiotics

• Penicillins, spectrum of activity: • Narrow: penicillin G, penicillin V, , , meticillin • Medium: ampicillin, , • Broad: , , Classification of antibiotics ß-lactam antibiotics

• Basic penicillins: ◦ Acidolabile → (penicillin G), procaine benzylpenicillin, benzathine benzylpenicillin • G+ cocci & rods, G- cocci & spirochetes, Pasteurella sp., Bacteroides, Treponema pallidum, Borrelia burgdorferi Classification of antibiotics ß-lactam antibiotics

• Basic penicillins: ◦ Acidostabile → fenoxymethylpenicillin (penicillin V), • G+ cocci & rods, G- cocci & spirochetes, Pasteurella sp., Bacteroides Classification of antibiotics ß-lactam antibiotics

• Penicillins resistant to ß- lactamases: • Oxacillin, , meticillin, , , • Clavulanic acid + amoxicillin = co- amoxicillin (Amoksiklav, Augmentin) • , Staphylococcus sp. Classification of antibiotics ß-lactam antibiotics

• • Amoxicillin, ampicillin • Ampicillin + sulbactam = • faecalis, Listeria sp., G- rods Classification of antibiotics ß-lactam antibiotics

•

• Parenteral application

• + tazobactam = co- piperacillin

• also Classification of antibiotics ß-lactam antibiotics

•

• Ticarcillin + clavulanic acid = co-ticarcillin

• Broad spectrum of activity, also Pseudomonas aeruginosa Classification of antibiotics ß-lactam antibiotics

• Cephalosporins • Bactericidal activity

• I. generation Efficacy Efficacy on • II. generation on G- G+ cocci rises ↑ decreases ↓ • III. generation • IV. generation • V. generation Classification of antibiotics ß-lactam antibiotics

• Cephalosporins • I. generation • Escherichia, Klebsiella, Proteus • Oxacillin-sensitive G+ cocci (streptococci gr. A, S. aureus, pneumococci) • UTI, upper RTI, SSTI • , → p.o. • , → inj. Classification of antibiotics ß-lactam antibiotics

• Cephalosporins • II. generation • More resistant to ß-lactamases • G- rods (Haemophilus influenzae, Bacteroides fragilis) • axetil, → p.o. • Cefuroxime → inj. Classification of antibiotics ß-lactam antibiotics

• Cephalosporins • III. generation • G- • Penetration to central nervous system • → p.o. • , → inj. • , → Pseudomonas aeruginosa, Bacteroides fragilis • Moxalactam Classification of antibiotics ß-lactam antibiotics

• Cephalosporins • IV. generation • Only parenteral application • G-, staphylococci, Pseudomonas aeruginosa, enterococci • Life-threatening G- or mixed infections • , , Classification of antibiotics ß-lactam antibiotics

• Cephalosporins • V. generation • Only parenteral • G+, G-, Enterobacteriaceae, Pseudomonas aeruginosa, MRSA • Complicated infections of skin, community-acquired pneumonia • Ceftobirol, ceftarolin-fosamil (prodrug, with ) Classification of antibiotics ß-lactam antibiotics

• • • G- • Multiresistant strains´ nosocomial infections • Klebsiella pneumoniae • Chronic pulmonary Pseudomonas aeruginosa infections in CF • UTI • Neisseria spp. Classification of antibiotics ß-lactam antibiotics

• • (G- cocci, HAS), (meningococci, HAS), (HAP, UTI), (CAP, SSTIs)

• Imipenem + cilastatin • Multiresistant strains´ nosocomial infections, Klebsiella pneumoniae Classification of antibiotics ß-lactam antibiotics

• Other ß-lactams • : clavulanic acid • Inhibition of ß-lactamases • Clavulanic acid + amoxicillin = co- amoxicillin (Amoksiklav, Augmentin) • Clavulanic acid + tikarcillin = co- tikarcillin (Timentin) Classification of antibiotics ß-lactam antibiotics

• Other ß-lactams • Avibactam: inhibition of ß- lactamases

• Avibactam + ceftaroline = G-, pseudomonades Classification of antibiotics Tetracyclines

• Inhibition of proteosynthesis • Bacteriostatic activity • Very broad spectrum of activity: Mycoplasma, Actinomycetes, Chlamydia, Rickettsia, Spirochaeta, some protozoa • Tetracycline, doxycycline, minocycline Classification of antibiotics Aminoglycosides

• Inhibition of proteosynthesis • Bactericidal activity • Medium spectrum of activity: aerobic G-, Staphylococcus sp. • Parenteral application • Gentamicin, tobramycin, amicacin, netilmicin, isepamicin, streptomycin, spectinomycin • Neomycin, canamycin – local use Classification of antibiotics Macrolides

• Inhibition of proteosynthesis • Bacteriostatic activity • Medium spectrum of activity • Erythromycin, roxithromycin (G+, G- cocci, spirochetes, RTI), spiramycin (Toxoplasma), azithromycin (G-, protozoa), clarithromycin, telithromycin (G+, Chlamydia, Ureaplasma, Gardnerella, Borrelia, Legionella, Prevotella, Propionibacterium) Classification of antibiotics Lincosamides

• Inhibition of proteosynthesis • Bacteriostatic activity • Semi-broad spectrum of activity: G+, G-, Bacteroides, Fusobacterium, staphyloccoci • Lincomycin, clindamycin Classification of antibiotics Amfenicoles

• Inhibition of proteosynthesis • Bacteriostatic activity • Broad spectrum of activity: G+, G-, Mycoplasma, Rickettsia, Chlamydia • Chloramphenicol, tiamphenicol • Hematotoxicity Classification of antibiotics Polypeptide antibiotics

• Damage of cell membrane • Spectrum of activity: G-, also Pseudomonas aeruginosa • Poor resorption → local use • (G- infections of urine bladder, p.o. gut decontamination), B • – bactericidal activity, cell wall synthesis inhibition

• Capreomycin, viomycin – (2nd line antituberculotic), bacteriostatic activity Classification of antibiotics Glycopeptides

• Inhibition of cell wall synthesis • Spectrum of activity: Staphylococcus spp. (MRSA), Campylobacter jejuni, Enterococcus spp., Clostridium difficile G+ only • Bactericidal activity • Vancomycin, , (SSTI) • Nephrotoxicity, ototoxicity, neurotoxicity • VRE, GRSA

https://en.wikipedia.org/wiki/File:Vancomycin.svg Classification of antibiotics Ansamycines

• Inhibition of nucleic acid synthesis • Broad spectrum of activity – Staphylococcus, Enterococcus, Neisseria, Legionella, Haemophilus, Mycoplasma, Rickettsia, Chlamydia, Mycobacterium spp. • Bactericidal activity • Rifampicin, rifabutin, rifaximin Classification of antibiotics Streptogramins

• Pristinamycin • Quinupristin, dalfopristin • Inhibition of proteosynthesis • Bacteriostatic action • In combination bactericidal on G+, VRSA, VRE Classification of antibiotics Sulfonamides and pyrimidines

• Antimetabolites • Broad spectrum of activity – G+ (Streptococcus, Staphylococcus, Clostridium, Nocardia), G- (Legionella, Chlamydia), Toxoplasma, Plasmodium • Bacteriostatic activity • Local use • Sulfamethoxazole + trimethoprim = co-trimoxazole = synergic bactericidal activity Classification of antibiotics Sulfonamides and pyrimidines

• Antimetabolites • Broad spectrum of activity – G+, G-, Toxoplasma gondii, Leischmania, Pneumocystis jirovecii • Trimethoprim + pyrimetamin = treatment of malary • Trimethoprim + sulfonamide = bactericidal, infections of respiratory and urinary tracts, gut, Chlamydia (trachoma), brucellosis, nocardiosis Classification of antibiotics Nitroimidasoles

• Inhibition of nucleic acid synthesis • Broad spectrum of activity: anaerobes, Helicobacter pylori, Trichomonas spp., Giardia, Amoeba • Bactericidal activity • Metronidazole, ornidazole Classification of antibiotics Nitrofuranes

• Inhibition of proteosynthesis • Broad spectrum of activity: Staphylococcus, Streptococcus, Enterococcus, Escherichia, Klebsiella • Bacteriostatic activity • Urinary tract infections • Nitrofurantoin, nifuratel (Trichomonas, Giardia, Entamoeba) Classification of antibiotics Quinolones

• Inhibition of nucleic acid synthesis • Bactericidal activity • Classic quinolones, 1st generation: • Narrow spectrum of activity: G- enteric rods, cocci • Urinary tract infections • Nalidixic acid, oxolinic acid Classification of antibiotics Quinolones

• Inhibition of nucleic acid synthesis • Bactericidal activity • Fluoroquinolones, 2nd generation: • Broad spectrum of activity: G-, mycoplasma, legionella, chlamydia • Norfloxacin, perfloxacin, ciprofloxacin, ofloxacin Classification of antibiotics Quinolones

• Inhibition of nucleic acid synthesis • Bactericidal activity • 3rd generation: • Longer biological halftime • Broad spectrum of activity: G-, streptococci(G+) • Balofloxacin, levofloxacin (mycoplasma) Classification of antibiotics Quinolones

• Inhibition of nucleic acid synthesis • Bactericidal activity • 4th generation: • Parenteral application • Broad spectrum of activity: G-, G+ • Gemifloxacin, moxifloxacin Classification of antibiotics Oxazolidinones

• Linezolid, tedizolid • Inhibition of proteosynthesis • Reserved antibiotic • Infections of skin and skin structures, G+, including MRSA, VRE Classification of antibiotics Antimycobacterial drugs

• Therapy of Mycobacterium spp. infections • Intracellular pathogens • Long-term therapy → development of resistance • Combination of several drugs Classification of antibiotics Antituberculotis (tuberculostatics)

• Mycobacterium tuberculosis • – bacteriostatic, till bactericidal activity • Ethambutol – bacteriostatic activity • Ethionamide – MDR&XDR-TB in 5 combination • Pyrazinamide – bactericidal activity • In combination (rifampicin, capreomycin, cycloserin, clofazimine, ofloxacin, canamycin, amicacin, streptomycin) Classification of antibiotics Antituberculotis (tuberculostatics)

• Initial phase (2 months) – reduction of mycobacterial population; rifampicin, isoniazid, pyrazinamide, ethambutol • Continuation phase (4 months) – rifampicin, isoniazid Classification of antibiotics Antileprotics

• Mycobacterium leprae • Dapsone – bacteriostatic chemotherapeutic, antimetabolite (inhibition of dihydrofolic acid synthesis) • Clofazimine – blocking the template functions of DNA • Rifampicin - ansamycine Classification of antibiotics Local antibiotics

• Mupirocin – broad spectrum bactericidal antibiotic • Fusidic acid – G+ cocci • Neomycin + bacitracin - bactericidal activity • Sulfadiazine, sulfathiazole - in combination with silver, skin burn infections • Metronidazole, erythromycin, clindamycin, nitrofurantoin • Classification of antibiotics New antibiotics

More than 30-year void in discovery of New research new types of antibiotics and level of coordination that goes beyond anything that now exist in academia, industry, or government.

http://www.pewtrusts.org/en/research-and-analysis/reports/2016/05/a-scientific-roadmap-for-antibiotic-discovery Classification of antibiotics New antibiotics

• - lipopetide • Mode of action not well understood (disruption of cell wall) • Only G+ • Treatment of MRSA-linked complicated skin and skin- structure infections and bacteraemia Classification of antibiotics New antibiotics

• Teixobactin (2015) ◦ Inhibition of cell wall synthesis ◦ Isolated from bacterium Eleftheria terrae ◦ Effective against MRSA, M.tuberculosis ◦ In testing

Ling et al., 2015 http://www.northeastern.edu/news/2015/01/a-new-antibiotic-teixobactin/ Classification of antibiotics New antibiotics

• Lugdunin (2016) ◦ Mode of action not known ◦ Isolated from human nasal bacterium Staphylococcus lugdunensis ◦ Bactericidal against glycopeptide intermediate resistant S. aureus, MRSA, VRE ◦ In testing

Zipperer et al., 2016 http://www.nature.com/news/the-nose-knows-how-to-kill-mrsa-1.20339 Classification of antibiotics New antibiotics

• Pseudouridimycin (2017) ◦ Inhibition of RNA syntase ◦ Soil bacteria Streptomyces sp. ◦ Analogue of UTP ◦ Effective against G+, G-, resistant strains

Chellat & Reidl, 2017 Classification of antibiotics New antibiotics

• Vankomycin 1,0 (1958): MRSA • Vankomycin 3,0 (2017): VRE 1. Binding to D-Ala and D-Lac in peptidoglycan → cell wal synthesis inhibition 2. Inhibition of transglycosylase → cell wal synthesis inhibition 3. Induces cell membrane permeability

Okano et al., 2017 Classification of antibiotics New antibiotics

• Odilorhabdins (2018) • Inhibition of proteosynthesis (binding small subunit of ribosome→induction of miscoding) • Activity against on G+ & G- (including CRE) • Absence of toxicity in murine model • Low frequency of bacterial resistance

Pantel et al., 2018 Classification of antibiotics New antibiotics

• G0775: chemicaly modified arylomycins (2018) • Inhibition of bacterial type I signal peptidase • Activity against G-, including MDR • Excellent preclinical efficacy, low vulnerability to spontaneous resistance

Smith et al., 2018 Classification of antibiotics New antibiotics

• Malacidins (2018): macrocyclic lipopeptide • Inhibition of cell wall synthesis • Active against MDR pathogens, including MRSA, GISA/GRSA • Low rate of resistance development

Hover et al., 2018 Thank you for your attention!

„Antibiotics: Handle with Care.“ 18-24 November 2019 World Antibiotic Awareness Week Abbreviations

• aa: • CAP: Community Acquired Pneumonia • CF: Cystic Fibrosis • CRE: Resistant Enterobacteriaceae • GRSA: Glycopeptide Resistant Staphylococcus aureus • GISA: Glycopeptide Intermediate Resistant Staphylococcus aureus • HAP: Hospital Acquired Pneumonia • HAS: Hospital Acquired Septicaemia • MDR-TB: MultiDrug Resistant TuBerculosis • MRSA: Resistant Staphylococcus aureus • PABA: para-aminobenzoic acid • RTI: Respiratory Tract Infections • SSTI: Skin and Soft Tissues Infections • UTI: Urinary Tract Infections • VRSA: Vancomycin Resistant Staphylococcus aureus • VRE: Vancomycin Resistant enterococci • XDR-TB: Extended Drug Resistant TuBerculosis