Antibiotics and Antibiotic Resistance

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Index

A Antifolates. See also specific drugs AAC(60)-Ib-cr, 185 novel compounds, 378–379 ACHN-975 overview, 373–374 clinical studies, 163–164 resistance mechanisms medicinal chemistry, 166 sulfamethoxazole, 378 structure, 162 trimethoprim, 374–378 AcrAB-TolC, 180 Apramycin, structure, 230 AcrD, 236 Arbekacin, 237–238 AdeRS, 257 Avibactam, structure, 38 AFN-1252 Azithromycin mechanism of action, 148, 153 resistance, 291, 295 resistance, 153 structure, 272 structure, 149 Aztreonam, structure, 36 AIM-1, 74 Amicoumacin A, 222 Amikacin B indications, 240 BaeSR, 257 structure, 230 BAL30072, 36 synthesis, 4 BB-78495, 162 Aminoglycosides. See also specific drugs BC-3205, 341, 344 historical perspective, 229–230 BC-7013, 341, 344 indications, 239–241 b-Lactamase. See also specific enzymes mechanism of action, 232 classification novel drugs, 237 class A, 67–71 pharmacodynamics, 238–239 class B, 69–74 pharmacokinetics, 238–239 class C, 69, 74 resistance mechanisms class D, 70, 74–77 aminoglycoside-modifying enzymes evolution of antibiotic resistance, 4 acetyltransferases, 233–235 historical perspective, 67 nucleotidyltransferases, 235 inhibitors phosphotransferases, 235 overview, 37–39 efflux-mediated resistance, 236 structures, 38 molecular epidemiology, 236–237 nomenclature, 67 overview, 17, 233 b-Lactams. See also specific classes and antibiotics ribosomal RNA modifications, 235–236 Enterococcus faecium–resistancemechanisms, 52–54 spectrum of activity, 230–232 mechanism of action, 24–25, 45–46, 65–66 structures, 230 monocyclic b-lactams, 36–37 targets, 17 Mycobacterium tuberculosis–resistance Amoxicillin, structure, 27 mechanisms, 56–57 AmpC, 74 penicillin-binding proteins Ampicillin, structure, 26 Enterococcus faecium,52–53 Antibiotic resistance dating Mycobacterium tuberculosis,56 challenges, 9 peptidoglycan assembly enzymology, 46–48 experimental evidence for old resistance, 11–12 Staphylococcus aureus,54–55 phylogenetics, 11 Staphylococcus pneumoniae sequencing techniques, 9–10 overview, 48–49 technology impact, 10–11 resistance proteins, 49–52 Antibiotic restriction, guidelines, 5 targets, 45–46, 65–66

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© 2016 by Cold Spring Harbor Laboratory Press. All rights reserved. This is a free sample of content from Antibiotics and Antibiotic Resistance. Click here for more information on how to buy the book. Index b-Lactams. See also specific classes and resistance, 164–165 antibiotics (Continued) structural basis of species specificity and kinetics, popularity, 23–24 166–167 Staphylococcus aureus–resistance structure, 162 mechanisms, 54–56 Chloramphenicol, 17, 311–312, 316–317, 321–322, 326 Staphylococcus pneumoniae–resistance 5-Chloro-2-phenoxyphenol mechanisms, 48 mechanism of action, 148 targets and resistance mechanisms, 17, 66–67 structure, 149 Biapenem, 35 Chlortetracycline, structure, 248 Blasticidin S, 225 Ciprofloxacin. See Fluoroquinolones Brachybacterium, phylogenetic analysis of resistance, 12 Clarithromycin resistance, 295 structure, 272 C Clavulanic acid, 38 Capreomycin, 223 Clindamycin, 311, 316 Carbapenems. See also specific drugs Clomocycline, 248 historical perspective, 34–36 Clostridium difficile types and structures, 35 clinical features of infection, 383–384 Carbenicillin, 27 fidaxomicin therapy. See Fidaxomicin Cathelicidin microbial peptide (CRAMP), 130 LFF571 therapy. See LFF571 Cefaclor, 29 rifaximin therapy, 209 Cefazolin, 30 Cloxacillin, 26 Cefdinir, 30 CmlB1, 326 Cefepime, 31 Cmr, 323 Cefixime, 29 CRAMP. See Cathelicidin microbial peptide Cefoperazone, 30 CTX, 70 Cefotaxime, 30 Cycloheximide, 344 Cefoxitin, 32 Cystic fibrosis (CF), tobramycin therapy, 240 Cefpoxime, 29 Ceftaroline, 31 Ceftazidime, 31 D Ceftibutin, 29 Dalbavancin Ceftobiprole, 31 historical perspective, 83 Ceftolozane resistance mechanisms, 90–91 structure, 31 structure, 82 uses, 33 Dalfopristin, 310–311, 316 Ceftriaxone, 30 Daptomycin Cefuroxime, 30 historical perspective, 109–110 Cephalexin, 29 mechanism of action, 112–114 Cephalosporin, 357 resistance Cephalosporins. See also specific drugs Enterococcus faecalis, 118–120 historical perspective, 28, 33 Enterococcus faecium, 118–120 types and structures, 29–32 overview of mechanisms, 17, 114 uses, 28, 33 Staphylococcus aureus, 114–118 CF. See Cystic fibrosis structure, 110–111 Cfr, 347 synthesis, 110–112 cfr, 327–329 targets, 17 CG400462 Demethylchlorotetracycline, 248 mechanism of action, 148 DHFR. See Dihydrofolate reductase structure, 149 DHPS. See Dihydropteroate synthase CG400549 Dihydrofolate reductase (DHFR), 373–375, 377 mechanism of action, 148, 153 Dihydropteroate synthase (DHPS), 373–374, 378–379 structure, 149 DIM-1, 74 CHIR-090 Dityromycin, 222 bacterial defense effects of inhibition, 169 Doripenem, 35 medicinal chemistry, 165–166 Doxycycline, 248

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E FIM-1, 74 eat(A), 325 Florfenicol, 311–312, 315, 317, 326 Edeine, 218 Fluoroquinolones Elongation factors historical perspective, 173–174 fusidic acid targeting of Ef-G, 18, 225, 355, 360–363 mechanism of action, 174–177 LFF571 targeting of Ef-Tu, 389–392 resistance translation, 219–225 mechanisms EmrR, 181 permeation alterations, 178–182 Enoyl-acyl carrier protein reductase (FabI) inhibitors. plasmid-mediated resistance, 182–186 See also specific inhibitors PMQR determinants, 186 bisubstrate inhibitors, 148–152 target enzyme mutational alteration, mechanism of action, 18 177–178 NAD(P)–FabI-binding inhibitors overview, 4, 17 product complex binders, 152–153 targets, 17 substrate complex binders, 153–154 Folate pathway inhibitors. See Antifolates prospects for study, 154–155 FomA, 104 types and structures, 146–147 FomB, 104 Enterococcus faecalis, daptomycin resistance, 118–120 FosA3, 103, 105 Enterococcus faecium FosB, 103 b-lactam-resistance mechanisms, 52–54 Fosfomycin daptomycin resistance, 118–120 historical perspective, 97–98 Eravacycline mechanism of action, 98–100 clinical studies, 262 resistance development, 249 clinical considerations structure, 248 combination therapy, 104–105 Ere(A), 287–288 overview, 104 Ere(B), 287–288 modifying enzymes, 102–104 Erm, 272, 274, 281–283 mutational resistance, 100–101 Ertapenem, 35 overview of mechanisms, 18 Erythromycin spectrum of activity, 98 resistance, 295 target, 18 structure, 272 uptake, 100 5-Ethyl-2-phenoxyphenol FosX, 104 mechanism of action, 148 fus genes, 364–366 structure, 149 Fusidic acid EttA, 347 mechanism of action, 18, 225, 355, 360–363 ExPortal, 131 pH effects and intracellular activity, 360–361 prospects for study, 369 resistance F cross-resistance with other antibiotics, 366 FabI inhibitors. See Enoyl-acyl carrier protein development, 363–364 reductase inhibitors dosing optimization for prevention, FDX. See Fidaxomicin 366–368 FepA, 180 mechanisms, 18, 363–366 FepR, 180 prevalence, 358–359 Fidaxomicin (FDX) spectrum of activity, 356–360 efficacy against Clostridium difficile, 386 structure, 356 historical perspective, 384–385 mechanism of action, 385–386 prospects for study, 392–393 G resistance GE2270A, 220 frequencies, 387 GE2832, 223 mechanisms, 18, 387–389 GE81112, 218 resistant Clostridium difficile features, 389 Gene transfer structure, 386 bacteria, 4–5 target, 18, 385 horizontal gene transfer, 18

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Genomics, antibacterial drug target identification, LFF571 16–17 historical perspective, 385 Gentamycin, 222 mechanism of action, 389–391 Gentamycin C1a, 230 prospects for study, 392–393 GES b-lactamases, 71 resistance GIM-1, 74 frequencies, 391–392 Glycopeptide antibiotics. See also specific antibiotics mechanisms, 391–392 antibacterial spectrum, 84 structure, 386 historical perspective, 83 Limecycline, 248 mechanisms of action, 84–87 Lincomycins, 17, 310–311 overview, 81, 83 Lincosamides. See also specific drugs resistance mechanisms, 87–91 indications, 310 structures, 82 mechanism of action, 313–315 GSK2251052, 19 prospects for study, 328, 330 GyrA, 177 resistance GyrB, 177 efflux genes multidrug transporters, 323 specific exporters, 323–325 H enzymatic inactivation, 319, 321 HE. See Hepatic encephalopathy mechanisms, 315, 317 Helvoic acid, 357 prevalence, 315–317 Hepatic encephalopathy (HE), rifaximin therapy, ribosomal mutations, 317–319 206–207 target site modifications and resistance, 327 structures, 311 Linezolid, 327 I Lipopolysaccharide (LPS) IBS. See Irritable bowel syndrome LpxC inhibitors. See LpxC inhibitors Iclaprim, 375, 378 modifications in polymyxin resistance, Imipenem, 35 132–137 IMP, 72–73 lmr genes, 324 InhA, 150 Lon protease, tetracycline resistance, 258 Initiation factors, translation, 216–219 LPS. See Lipopolysaccharide Irritable bowel syndrome (IBS), rifaximin therapy, LpxC inhibitors. See also specific inhibitors 205–206 adaptation to alteration of lipopolysaccharide Isoniazid synthesis, 167–168 mechanism of action, 148, 150 bacterial defense effects of inhibition, 168–169 resistance mechanisms, 150–152 clinical studies, 162–163 structure, 149 historical perspective, 160–162 lipid A biosynthesis, 159–160 medicinal chemistry, 165–166 J overview, 18 Josamycin, 273 Pseudomonas aeruginosa studies, 162 resistance, 164–165 structural basis of species specificity and K kinetics, 166–167 Kanamycin, 222 structures, 162 Kasugamycin, 218 lsa genes, 324–325 KatG, 150 Kirromycin, 220 Kitasamycin, 273 M KPC, 70–73 Macrolides. See also specific drugs indications, 271 mechanism of action, 272–273, 275–276 L resistance mechanisms Lefamulin, 341–342, 344–346 characterization of molecular Levofloxacin. See Fluoroquinolones mechanisms, 290–295

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Macrolides (Continued) fosfomycin resistance, 99 efflux isoniazid-resistance mechanisms, 150–152 Mef, 284–286 resistance overview, 3 Msr, 286–287 rifamycin management overview, 273, 275 rifabutin, 200 inactivation of drug rifampicin esterases, 287–288 latent tuberculosis prophylaxis, 201 phosphotransferases, 288–290 overview, 199–200 overview, 17, 272–275 rifapentine, 200 prospects for study, 295 Mycoplasma pneumoniae, macrolide resistance, 295 ribosomal modification cis-acting peptides, 283–284 N erm gene mutations, 281–283 ribosomal protein mutations, 280–281 Nafcillin, structure, 27 ribosomal RNA, 276–280 Nalidixic acid. See Fluoroquinolones Rlm methyltransferases, 284 NDM-1, 72–73 structures, 271–273 Negamycin, 222 surveillance of resistance, 291–294 Neomycin, 222–223 targets, 17 Neomycin B, 230 MarA, 254, 256 Nmc-A, 71 MdeA, 179 NorB, 179 MdfA, 182, 323 NorC, 179 Mecillinam applications, 28 O structure, 27 Oleandomycin, 272 Mef, 284–286 Omadacycline MepA, 180 clinical studies, 261–262 MepR, 180 development, 248–249 Methacycline, structure, 248 structure, 248 Methicillin, structure, 26 OmpC, 249, 255 Methicillin-resistant Staphylococcus aureus (MRSA) OmpF, 180, 249, 255 cephalosporin therapy, 33–34 OprF, 180–181 FabI inhibitor therapy and resistance, 152–153 OprJ, 181 genomics studies of resistance, 16 OprM, 180 lefamulin activity, 345 optrA, 327 macrolide resistance, 291 OqxAB, 185 penicillin-binding proteins, 55 Oritavancin Metronidazole, targets and resistance mechanisms, 17 historical perspective, 83 Metropenem, 35 mechanisms of action, 86 MexAB, 181 resistance mechanisms, 90–91 MgrA, 179 structure, 82 Midecamycin, 273 OXA b-lactamases, 75–77 Milkamycin, 310, 312 Oxacillin, structure, 26 Minocycline Oxazolidinones clinical studies, 259, 261 resistance mechanisms structure, 248 exporters, 326–327 Moxalactam, 32 overview, 17 Mph phosphotransferases, 289–290 target site modifications, 327–328 MRSA. See Methicillin-resistant Staphylococcus aureus targets, 17 Msr, 286–287 Oxytetracycline, 248 msr genes, 325 MUT0563999 mechanism of action, 148 P structure, 149 Pactamycin, 218 Mycobacterium tuberculosis Paromomycin, indications, 241 b-lactam-resistance mechanisms, 56–57 PatAB, 180

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Penicillin-binding proteins. See b-Lactams overview of mechanisms, 17, 131–132 Penicillins. See also specific drugs plasmid-mediated resistance, 138 historical perspective, 3, 25–28 polymyxin efflux, 138 types and structures, 26–28 prospects for study, 138–139 PF-5081090 stress responses, 137–138 clinical studies, 163–164 structure, 126 resistance, 165 synthesis, 126–127 Phenicols. See also specific drugs Pregnane receptor, rifaximin as effector, 204 indications, 312 Pristinamycin, 310, 312 mechanism of action, 313–315 Prontosil, 374 prospects for study, 328, 330 Propargyl-linked antifolates, 375, 379 resistance Prosthetic joint infection (PJI), rifampicin therapy, efflux genes 202–204 multidrug transporters, 323 Protein synthesis. See Ribosome specific exporters, 326–327 Pseudomonas aeruginosa enzymatic inactivation, 321–323 fosfomycin resistance, 101–102 mechanisms, 315, 317 LpxC inhibitor studies, 162 prevalence, 315–317 Puromycin, 344 ribosomal mutations, 317–319 target site modifications and resistance, 327–328 Q structures, 311 QepA, 185 PhoBR, 257 Qnr Piperacillin, structure, 27 origins, 183–184 Pirlimycin, 310–311, 316 quinolone resistance plasmids, 185–186 PJI. See Prosthetic joint infection structure and function, 182–183 Plague, historical perspective, 2 Quinupristin, 310–311, 316 Plazomycin, 237–238, 240 Pleuromutilins. See also specific drugs indications, 313 R mechanism of action, 17, 313–315, 341–342 RamA, 254, 256–257 overview, 339–340 RarA, 254 prospects for study, 328, 330 Release factors, translation, 224–225 resistance Relebactam, 38 efflux genes Resistome multidrug transporters, 323 environment and gene mobilization, 8–9 specific exporters, 324–325 overview, 4, 7–8 enzymatic inactivation, 323 Retapamulin, 311, 313, 341, 344 mechanisms, 17, 315, 317, 345–348 RG6080, 38 prevalence, 315–317, 348 Ribosome ribosomal mutations, 317–319 elongation of translation, 219–221 target site modifications and resistance, 327–328 fusidic acid interactions, 18, 225, 355, 360–363 spectrum of activity, 343–345, 348 initiation of translation, 216–219 structures, 311, 340–341 LFF571 interactions, 390–391 Polymyxin lincosamide–streptogramin–phenicol– historical perspective, 3, 126 pleuromutilin interactions indications, 127 mutations in resistance, 317–319 mechanism of action overview, 313–315, 341–342 bacterial respiration, 129–130 macrolide resistance and modifications cell division, 130–131 cis-acting peptides, 283–284 ExPortal, 131 erm gene mutations, 281–283 overview, 126–127 ribosomal protein mutations, 280–281 reactive oxygen species, 131 ribosomal RNA, 276–280 ribosome binding, 129 Rlm methyltransferases, 284 targets, 17, 128–129 peptide bond formation, 221–222 resistance sites, 215–216 lipopolysaccharide modifications, 132–137 structure, 215, 223

402

Ribosome (Continued) RobA, 254 termination and recycling, 224–225 Rolitetracycline, 248 tetracycline interactions Rosamicin, 273 binding site mutations and resistance, 250–251 Roxithromycin, 272 overview, 249–250 rpl genes, 319–321, 345–348 tetracycline ribosomal protection proteins, 251– RpoE, 137 252 RpoS, 137 translocation and EF-G, 222–223 RprXY, 257 Rifabutin. See also Rifamycins RPX7009, 38 minimum inhibitory concentrations, 197 pharmacology, 198 structure, 196 S tuberculosis management, 200 S-649266, 32 Rifampicin. See also Rifamycins sal(A), 325 Gram-positive bacteria infection management, 202 SatAB, 180 minimum inhibitory concentrations, 197 SdrM, 179 pharmacology, 198 SD sequence. See Shine–Dalgarno sequence prosthetic joint infection treatment, 202–204 Shine–Dalgarno (SD) sequence, 217 structure, 196 SHV, 70 target and resistance mechanisms, 18 Sig1, 151 tuberculosis management SIM-1, 74 latent tuberculosis prophylaxis, 201 SMB-1, 74 overview, 199–200 SME-1, 71 Rifamycins. See also specific drugs Solithromycin, 272 mechanism of action, 195–196 SoxS, 254 minimum inhibitory concentrations, 197 Spectinomycin, 222 peptic ulcer disease treatment, 201 Spiramycin, 273 pharmacology, 198 SPM-1, 74 prospects for study, 209–210 Staphylococcus aureus. See also Methicillin-resistant resistance potential, 196, 199 Staphylococcus aureus structures, 196 b-lactam-resistance mechanisms, 54–56 tuberculosis management daptomycin resistance, 114–118 rifabutin, 200 Staphylococcus epidermidis, triclosan rifampicin resistance, 153 latent tuberculosis prophylaxis, 201 Staphylococcus pneumoniae overview, 199–200 b-lactam-resistance mechanisms, 48 rifapentine, 200 penicillin-binding proteins Rifapentine. See also Rifamycins overview, 48–49 minimum inhibitory concentrations, 197 resistance proteins, 49–52 pharmacology, 198 Streptogramins. See also specific drugs structure, 196 indications, 310, 312 tuberculosis management, 200 mechanism of action, 17, 313–315 Rifaximin. See also Rifamycins prospects for study, 328, 330 Clostridium difficile management, 209 resistance gastrointestinal infection management, 204 efflux genes hepatic encephalopathy management, 206–207 multidrug transporters, 323 inflammatory bowel disease management, 204–205 specific exporters, 325 irritable bowel syndrome management, 205–206 enzymatic inactivation, 321 minimum inhibitory concentrations, 197 mechanisms, 17, 315, 317 pharmacology, 198 prevalence, 315–317 pregnane receptor effector, 204 ribosomal mutations, 317–319 resistance development, 207–209 target site modifications and resistance, structure, 196 327–328 traveler’s diarrhea management, 207 structures, 311 RNA polymerase, fidaxomicin interactions, 385, Streptomycin, 230 388–389 Sulbactam, 38

403

Sulfamethoxazole Tiamulin, 311, 313, 316, 339, 341, 344 development, 374 Ticarcillin, 27 resistance mechanisms, 378 Tigecycline structure, 375 clinical studies, 248, 261 Sulfonamides resistance, 257 historical perspective, 3 structure, 248 target and resistance mechanisms, 18 Timicosin, 273 TMB-1, 74 TMP. See Trimethoprim T Tobramycin, 230 Tazobactam, 38 TolC, 323, 344 TD. See Traveler’s diarrhea Topoisomerase IV inhibitors. See Fluoroquinolones Tebipenem, 35 Translation. See Ribosome Tedizolid, 327 Traveler’s diarrhea (TD), rifaximin therapy, 207 Teicoplanin Triclosan historical perspective, 83 mechanism of action, 148 mechanisms of action, 85–86 Staphylococcus epidermidis resistance, 153 resistance mechanisms, 90–91 structure, 149 structure, 82 Trimethoprim (TMP) Telavancin development, 374 historical perspective, 83 historical perspective, 3 mechanisms of action, 86–87 resistance mechanisms, 18, 374–378 resistance mechanisms, 90–91 structure, 375 structure, 82 targets, 18 Telithromycin, 272 Troleandomycin, 272 TEM, 70 Tuberculosis. See Mycobacterium tuberculosis Temocillin Tulathromycin, 272 applications, 28 Tylosin, 273 structure, 27 Tet proteins, 364–365 Tetracyclines. See also specific drugs, 248 U clinical studies Ureaplasma urealyticum, macrolide resistance, 295 eravacycline, 262 minocycline, 259, 261 omadacycline, 261–262 V historical perspective, 247–248 Valnemulin, 311, 313, 339, 341, 344 mechanism of action, 249 Vancomycin resistance mechanisms historical perspective, 83 efflux, 252–253 mechanisms of action, 85 enzymatic inactivation, 253–254 resistance mechanisms, 87–91 multidrug-resistance mechanisms structure, 82 AraC transcriptional activators, 254–257 Vancomycin-resistant Enterococcus (VRE), 87 intrinsic efflux, 258–260 Vancomycin-resistant Staphylococcus aureus Lon protease, 258 (VRSA), 87 two-component systems, 257–258 vat genes, 321 overview, 17 Veterinary antibiotics, limiting of usage, 5 ribosome interactions vga genes, 324, 345, 347 binding site mutations and resistance, 250–251 vgb genes, 321 overview, 249–250 Vibrio cholera, phylogenetic analysis of resistance, 12 tetracycline ribosomal protection proteins, 251– VIM, 72–74 252 Viomycin, 223 structures, 248 Virginiamycin, 310, 312 targets, 17 Viridin, 357 uptake, 249 VRE. See Vancomycin-resistant Enterococcus Thiamphenicol, 311–312, 321 VRSA. See Vancomycin-resistant Staphylococcus aureus

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