539 Index a aminobenzimidazole ureas 282 A2062 516 aminocoumarins 17, 19–20, 86, 87, A83016F 445 276–280, 284 acidic phospholipids 187 aminoglycoside acetyltransferases (AACs) acitretin 358, 364, 365 83–84, 461 actinonin 412, 415, 417–418 aminoglycoside phosphotransferases (APHs) acyl homoserine lactone (AHL) 241, 84, 459, 461 251–253 aminoglycosides 1–3, 76, 84, 86, 88, 93, 97, acyltransfer 83–84 359–361, 373, 376, 453–455, 502 adenosine diphosphate – A-site switch locking in ‘‘on’’ state (ADP)-ribosyltransferase 85 459–461 adriamycin RDF (doxorubicin) 342, 344 – binding affinity and eluding defense AFN-1252 203 mechanisms 461–462 AgrC/AgrA 248–247, 249 – binding pocket recognition 459 agrocin 394, 395 – binding to antibiotic-resistant bacterial ajoene 245, 252, 253 mutant and protozoal cytoplasmic A sites albicidin 275 464 2-alkoxycarbonylaminopyridines 161–164 – binding to human A sites 464–465 amicetin 358, 361, 362 – chemical structures 455 amidases 80 – molecular recognition by bacterial A site amikacin 457, 462, 463 458–459 aminoacyl-tRNA synthetases (aaRSs) 388 – nonaminoglycoside antibiotic targeting of A – classification 389–391 site 466 – enzymatic mechanism of action 388–389 – not targeting A site 465–466 – fidelity and proof reading 391–392 – secondary structures of target A sites 455, – transamidation pathway 392 458 aminoacyl tRNA synthetase inhibitors – semisynthetic aminoglycosides binding 387 463–464 – mupirocin 387, 393–395, 403 – targeting A site with different modes of – novel inhibitors in clinical development action 465 399–403 amphomycin 8, 11 – old and new compounds with aaRS amphotericin B 198 inhibitory activity 393–399 ampicillin 230 – resistance development 403 amycolamicin 281 – selectivity over eukaryotic and mitochondrial AN2690 (tavaborole) 400, 401–402 counterparts 404 anisomycin 361 aminoalkyl pyrimidine carboxamides (AAPCs) ansamycins 15–16, 302–304 44 anthralin 358, 365 Antibiotics: Targets, Mechanisms and Resistance, First Edition. Edited by Claudio O. Gualerzi, Letizia Brandi, Attilio Fabbretti, and Cynthia L. Pon. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA. 540 Index antibacterial discovery 23 bacterial cell-to-cell chemical signaling – cell entry 31–32 interference 241–242 – clinically used drug classes and sources 33 – non-TCSs targeting biofilm formation and – computational chemistry, virtual screening, quorum sensing in Pseudomonas spp. SBDD, and FBDD 42–45 250–253 – natural products 40–42 – two-component systems (TCSs) – problems 24 – – case studies as drug targets 243–246 – screening strategies 32 – – nonessential systems targeting 246–250 – – chemical collections 38–40 – – potential anti-infective targets 242–243 – – empirical screens 32–34 bacterial cell-wall precursor chemical ––in vitro screens for single-target inhibitors composition reprogramming 89 37–38 bacterial dynamin-like protein (BDLP) 157 – – phenotypic whole-cell screens 34–37 bacterial membrane 217–219 – target choice and essentiality 24–26 – efflux barrier 222–223 – target choice and resistance 26–31 – efflux blocking 225–229 antibiotic transferases 83–86 – efflux systems 92–94 antimicrobial peptides (AMPs) 183, 187, 190, – – major facilitator superfamily (MSF) 194, 198, 201 94–96 antipsoriatic compounds 364–366 – – ATP-binding cassette (ABC) superfamily apolipoprotein B 247, 248, 249 94 apramycin 461, 456, 457, 460, 462, 464 – – multidrug and toxic compound extrusion 7 ArmA/Rmt (m G1405) 377, 380 (MATE) family 97–98 arotinoids 364 – – resistance-nodulation division (RND) artesunate 229 superfamily 96–97 arylpiperidines 101 – – small multidrug-resistance family (SMR) ATPase-domain inhibitors 276 96 – GyrB and dual-targeting GyrB/ParE ATPase – influx increase 224–225 inhibitors 281–284 – natural products as efflux modulators – natural products 276–281 228–229 ATP-binding cassette (ABC) superfamily 94 – outer membrane barrier and porin aurodox 445 219–221 autoinducers (AIs) 241 – targeting 183–184 avilamycin 415, 421 – – bactericidal and low potential for azdimycin 445 resistance development 189–190 azetidinone 3 – – dormant infections treatment 184–185 azithromycin 514–515 – – fatty acid and phospholipid biosynthesis aztreonam 227 inhibition 203 azytromycin 13 – – new approaches to identify compounds killing dormant bacteria 196 b – – prevent and kill dormant bacteria bacterial cell division 152 185–186 – cytoskeleton proteins 157 – – target essentiality and selectivity – FtsZ structure and assembly properties 186–188 152–153 bactoprenol phosphate 145–146 – proteins involved in septum formation battacin 224 156 benzimidazoles 169, 281, 282 – proteins regulating FtsZ assembly benzoxaboroles 401, 403 155–156 benzoxazinorifamycins 15 – Z-ring 153–155 berberine 162, 167 bacterial cell partitioning inhibitors 151 β-galactosidase 528 – cell division proteins as therapeutic targets β-lactams 3–4, 75, 80, 81, 96, 97, 185, 218, 158, 170 221, 223, 229 – FtsZ as therapeutic target 158–170 – resistome of P. aeruginosa 98 Index 541 – acquired antibiotic resistance in S. aureus chloramphenicol 57, 75, 76, 80, 84, 95, 97, 98–100 117, 220, 223, 228, 361, 373, 374, 471, 472, BI-88E3 527, 530 473, 474, 475–476, 477, 478, 480, 481 biofilms 184–186, 190–196, 241, 243, 249 chloramphenicol acetyltransferases (CATs) – challenges with membrane-active agents 84 196 chlorogenic acid 162, 170 – genetic resistance 199–200 chloroquine 267 – pharmacological 198–199 chlorpromazine 228 – spectrum of activity 197–198 CHP-105 527, 530 – test methods 197 chrysophaentins 162, 169 – therapeutic use of membrane-damaging chuangxinmycin 394, 395 agents against biofilms 190–196 cinnamic acid 170 BioFlux systems 197 ciprofloxacin 95, 185, 223, 227, 266, biosynthetic medicinal pathway 66 267–268, 271–272, 275, 285, 286 bisbenzimide 342, 344 cispentacin 394, 396 blasticidin S 358, 361, 362, 471, 472, 473, clarithromycin 514 478–479 clavulanic acid 4, 101, 224 borrelidin 394, 395 clerocidin 263, 275, 287 clindamycin 75, 85, 401, 473, 474, 478, 481 c clofazimine 187, 192, 195, 201 caffeic acid 170 clorobiocin 277, 280 calcipotriol 358, 364, 365 Clostridium difficile infection (CDI) 202, 312, capistruin 302, 309 399–401 caprazamyins 135 co-chaperones 525, 527 capreomycin 497 colistins 8, 10, 197, 222, 224, 531 2-carbamoyl pteridine 163, 164 connective polypeptide 1 (CP1) 389 carbapenems 75, 81, 100, 218 corallopyronin 300, 303, 305, 311 cardiolipin 187, 188 coumermycin 277 carvacrol 225 covalent modifications on lipopolysaccharide CB183,315 202 core 92 CBR703 series 300, 301, 302, 305, 309–310 crescentin 157 c-di-GMP(bis-3 -5 -cyclic dimeric guanosine CRS3123 399–401, 404 monophosphate) riboswitch 331–334, 345 CSA-13 192, 195, 197 cefepime 221 curcumin 159, 162, 166 cefotaxime 221 cyclic peptides 8–11 cefpirome 221 cycline antibiotics 228 cell-wall synthesis inhibitors cycloheximide 500–501 – bactoprenol phosphate 145–146 cycloserine 164 – MraY inhibitors 134–137 cyclothialidines 276, 280 cell wall synthesis lipid II targeting cytokinesis 151, 153, 154, 156, 158, 170 compounds – enduracidin 143, 144 d – glycopeptides 134, 137–139, 146 dalbavancin 137, 138, 139, 187, 191, – lantibiotics 134, 139–143, 146 193–194, 199 – ramoplanin 134, 142, 143, 144, 146 dalfopristin 473, 482, 483, 515 Centers for Disease Control (CDC) bioreactor daptomycin 1, 9, 11, 57, 59, 65, 77, 91–92, 197 183, 187–188, 189, 190, 191, 193, 195, 198, cephalosporins 75, 80, 96, 97, 221, 224 199, 202–203, 248 ceragenins 194, 197 daunomycin 95 cerulenin 203 defensins 145, 202 cethromycin 12, 15 delafloxacin 271, 287 chelocardin 342, 344 15-deoxyspergualine 527 ChemBridge™ 303, 313 Dermofural 425, 428 chitosan 194 dichamentin 162, 166 542 Index difimicin 14, 15 ertapenem 218 dihydropteroate synthetase (DHPS) 77, 88 erythromycin 12, 13, 57, 75, 78, 81, 85, 88, diminazene aceturate 342, 344 95, 99, 227, 363, 373, 381, 474, 478, DinF protein 97–98 512–513, 514, 515, 516, 518 dityromycin 497 ethambutol 164 DNA gate inhibitors 265, 266 ethidium bromide 95, 99 – ATPase domain inhibitors 265, 266, eugenol 170 276–282 evernimicin 415, 421 – NBTIs 263, 265, 272–274, 287–288 – quinolones and related compounds 263, f 265, 267–272, 273–274, 275, 276, 284, factumycin 445 287–288 Fas II inhibitors 203 DnaK 525–528 fatty acid and phospholipid biosynthesis – cooperation with HtpG 530–531 inhibition 203 – in vivo screening of compounds targeting fatty acylbenzamides 530 528 ferulic acid 170 doripenem 218 fidoxamicin 400 double-sieve model 391 FtsZ D-peptides 530 – filamentous temperature-sensitive Z 152 – proteins regulating assembly 155–156 e – structure and assembly 152–153 edeine 413, 415, 423, 425, 426–427 FtsZ as therapeutic target efflux blocking 225–226 – identfication of antibacterial agents – barrier 222–223 158–161 – chemical response 226–228 – inhibitors 161–170 – natural products as efflux modulators – status of FtsZ-targeting compounds 228–229 172–173 efflux systems 92–94 fitness – ATP-binding cassette (ABC) superfamily – absolute 111 94 – cost and genetic background 120 – major facilitator superfamily (MSF) 94–96 – cost and regulation of resistance expression – multidrug and toxic compound extrusion 118 (MATE) family 97–98 – cost in clinical isolates 114–115 – resistance-nodulationdivision (RND) – cost of plasmid-borne resistance 117 superfamily 96–97 –costofrif resistance 114–117 – small multidrug-resistance family (SMR) –costofstr resistance 112–113 96 – – restrictive vs non restrictive phenotypes efrotomycin 445 113 elongation factor (EF-Tu) inhibitors 437 – cost