539

Index

a aminobenzimidazole ureas 282 A2062 516 17, 19–20, 86, 87, A83016F 445 276–280, 284 acidic phospholipids 187 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 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 -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 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 393–399 230 – 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 94 461, 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 184–185 514–515 – – fatty acid and phospholipid biosynthesis 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 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, 514 478–479 4, 101, 224 borrelidin 394, 395 clerocidin 263, 275, 287 75, 85, 401, 473, 474, 478, 481 c 187, 192, 195, 201 caffeic acid 170 277, 280 calcipotriol 358, 364, 365 Clostridium difficile infection (CDI) 202, 312, capistruin 302, 309 399–401 caprazamyins 135 co-chaperones 525, 527 497 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, 197 221 curcumin 159, 162, 166 221 cyclic peptides 8–11 221 cycline 228 cell-wall synthesis inhibitors cycloheximide 500–501 – bactoprenol phosphate 145–146 164 – MraY inhibitors 134–137 cyclothialidines 276, 280 cell wall synthesis II targeting cytokinesis 151, 153, 154, 156, 158, 170 compounds – enduracidin 143, 144 d – glycopeptides 134, 137–139, 146 137, 138, 139, 187, 191, – 134, 139–143, 146 193–194, 199 – 134, 142, 143, 144, 146 dalfopristin 473, 482, 483, 515 Centers for Disease Control (CDC) bioreactor 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 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, 15 218 dihydropteroate synthetase (DHPS) 77, 88 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 497 164 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 170 218 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 of transposon-acquired resistance – enacyloxins 437, 438–444, 447 117–118 – GE2270A 437, 438, 439, 440, 441, 442, 447, – cost of van resistance 118 448–449 – Darwinian 111 – kirromycin 438, 439, 440, 441, 442, 443, – effect of physiology, metabolism, lifestyle on 444–446, 447, 448 fitness 119–120 – pulvomycin 437, 438, 439, 440, 441. 442, – genetic factors affecting fitness 112–118 444, 446–448, 449 – relative 111 empedopeptin 134, 143, 144, 146 – reproductive rate 111 EmrB 93, 95 – selective advantage of str, rif and MD enacyloxins 437, 438–444, 447 resistance 119 enduracidin 143, 144 fitness estimation methods 110–112 95 – Bayesian computation 112 5-epi- 343, 344 – epidemiological 111 epoxidases 80, 81 – in animal models 111 ErmC 376, 379, 381 – in vitro 111 Index 543

flavonoids 56 GTP analogs 164–165 flippase domain 199 guanine riboswitches 329, 331 florfenicol 95, 100 gyramides 286, 287 fluorescence resonance energy transfer GyrB and dual-targeting GyrB/ParE ATPase (FRET) studies 492, 495 inhibitors 281–284 fluorescent recovery after photobleaching (FRAP) 153 h fluoro-phenyl-styrene- (FPSS) hamamelitannin 245, 249 314 heat-shock proteins 526, 531 fluoroquinolones 76, 78, 87, 93, 95, 97, 98, heneicomycin 445 99, 196, 217, 222, 223, 224, 227, 267 heteroaryl isothiazolones (HITZs) 272, 287 – acquired resistance 100 high-throughput screening (HTS) 24, 32, 36, – development and action mechanism 38, 39, 40, 42, 43, 44, 53–54, 64, 302, 303, 267–271 307, 309, 313, 343, 344, 345, 346, 397, 398, – phase II 271 399 FMN riboswitches 334–335 His-kinase inhibitors 101 folate metabolism inhibitors 412, 414–416 histidine kinase (HK) 242, 243, 246, 247, foldosome 530 248–250 friulimicin 8, 9–11, 134, 144, 145–146 horizontal and vertical transmission of FsrC/FsrA 247, 249 resistance genes 74–79 furanomycin 394, 395 horizontal gene transfer (HGT) 109, 126, 128 furanones 252, 253 HSP70 525–528 Furvina 415, 423, 425, 426, 428–429 – DnaK and HtpG cooperation 530–531 95, 97, 99, 190, 492, 493, 494, – drugging 528, 529–530 498, 499–500, 501, 503 – in vivo screening of compounds targeting DnaK 528 g HSP90 drugging 531 GAL analogs 162, 165 HtpG gambogic acid 531 – cooperation with DnaK 530–531 ganefromycin 445 human gut model 202 gatifloxacin 196 hydrazinopyrimidines 418 GE2270A 437, 438, 439, 440, 441, 442, 444, hydrolytic enzymes and antibiotic resistance 447, 448–449 80 GE23077 300, 303, 305, 314 – β-lactamases 81, 98, 101 GE81112 413, 415, 423, 424–425, 426–428 – epoxidases 80, 81 GE82832 495, 497 – esterases 81 geldanamycin 527, 531 – proteases 83 geneticin 457, 460, 461, 462, 464 2hydroxy-5-benzylisouvarinol-B 162, 166 genome mining in natural product discovery 462, 465, 495–496, 497, 500 66–67 85, 100, 358, 359, 360, 374, 376, i 378, 379, 456, 457, 461, 462, 494, 496, 502, iberin 245, 253 527, 530 29 geraniol 229 icofungipen 394, 397 geranylgeranylacetones 530 IF2 inhibitors 418–421 glycopeptides 75, 89, 100–101, 134, imidazopyridines 281, 282 137–139, 146 218, 220, 221, 222 glycopeptides-dalbaheptides 4–6 indazoles 281 glycosyltransferases 85–86 indole-3-glycerol phosphate synthase (IGPS) D 4 245 gramicidin S 4, 8, 9–10, 342, 344 indolmycin 394–395, 403 granaticin 394, 395 internal ribosome entry site (IRES) GSK1322322 415, 418 501 GSK2251052 (AN3365) 400, 401–403 isoalloxazine 334 544 Index

164, 169, 200, 203 lysine riboswitch 327, 337–339 isothermal titration calorimetry (ITC) 160, lysylphosphatidylglycerol (LPG) 199 167 isothiazolones 272 m isotretinoin 364 macrolactones – difimicin 14, 15 j – 12, 13, 15 JNJ-Q2 266, 271, 287 macrolide esterases 75, 81 macrolide peculiar behavior, on bacterial k RNase P 363–364 kanamycin 57, 84, 95, 99, 117–118, 164, 358, macrolide phosphotransferases 84–85 359, 360, 456, 457, 460, 461, 462, 463 macrolides 12, 13, 15, 57, 75, 80, 81, 85, 88, kasugamycin 413, 415, 423–427, 429, 466 93, 94–95, 97, 99, 376, 378, 379, 380 13 major facilitator superfamily (MSF) 93, kibdelomycin 263, 266, 280–281, 287 94–96 kirromycin 437, 438, 439, 440, 441, 442, 443, mannopeptimycin 134, 143, 144, 145, 146 444–446, 447, 448 MdfA 94–95 kirrothricin 445 melime 194 KsgA 376, 382, 425 menaquinone 201 218 l mersacidin 140, 141, 142 L-681,217 445 87, 88, 98, 99 labilomycin 446 methicillin-resistant Staphylococcus aureus lactimidomycin 501 (MRSA) 34, 37, 87, 88, 95, 98, 99, 100, 242, lankacidin 515, 516 245, 248, 249 lankamycin 515, 516 methionyl-tRNA formyltransferase 417 lantibiotics 4, 6–8, 75, 83, 134, 139–142, 146 methylene blue 530 lantipeptides. See lantibiotics methyltransferases 75, 76, 88, 340, 375–380, LasR 251, 252, 253 476 lasso peptides 308–309 – integration into ribosome biogenesis LED209 245, 247, 248, 253 pathway 380–381 levofloxacin 267, 527 400–401 75, 85, 95, 361, 471, 478, 480 microcin C 395 17, 18, 376, 378, 380, 472, 473, microcin J25 300, 302, 308 477–478 micrococcin 13, 421, 498–499 linear peptides 4 194 – glycopeptides-dalbaheptides 4–6 Min proteins 155 – lantibiotics 6–8 MKT-077 530 1, 16, 17, 66, 75, 95, 98, 100, 248, mocimycin 445 472, 473, 474, 476–477, 478, 481 moxifloxacin 185, 196, 266, 267, 268, 270, lipiarmycin 300, 301, 303, 304, 305, 271 312–313, 316 MraY and MyrA inhibitors 133, 134–137, lipid II targeting compounds 137 146 – glycopeptides 134, 137–139, 146 MreB and PreB inhibitor 157, 172 – lantibiotics 134, 139–142, 146 multidrug and toxic compound extrusion – enduracidin 143 (MATE) family 93, 97–98 – ramoplanin 134, 142, 143, 144 multidrug resistance (MDR) 79, 84, 85, 88, lipid tail 143 92, 93, 94, 96, 97, 99, 101, 220, 223, 225, lipoglycopeptides 187, 188, 193, 199–200 226, 227, 229, 230 lipopeptide resistance 91–92 multiple drug transporter Mdt(A) 94–95 liposidomycins 135 mupirocin 124, 125, 387, 393, 394–395, 403 lividomycin 456, 457, 460, 461, 462, 464 muraymycins 135–136, 137 LmrA 93, 94 mureidomycins 135–136 lotilibcin 9, 11 MX-2401 lipopeptide 189 Index 545 myricetin 530 orthosomycins 413, 420–421 myxobacteria 60 OTBA ((3-{5-[4-oxo-2-thioxo-3-(3-trifluoro- myxopyronin 300, 303, 305, 310–313 methyl-phenyl)-thiazolidin-5-ylidene- methyl]-furan-2-yl}-benzoic acid 162, n 167–168 N-3-oxo dodecanoyl-L-homoserine lactone outer membrane (OM) 217, 219 (OdHL) 251, 252, 253 – barrier and porin involvement 219–221 93, 95, 266, 267 oxazolidinones 16–18, 97, 100, 376, 380, natural compounds/products 32–38, 40–42, 471, 473, 476–477 53–68, 225, 228–229, 266, 276, 280–281, 95 286, 376 – antimicrobial activities 63–65 p – as continuing source of inspiration 65–66 pacidamycins 135 – challenge to find novel antibiotics from new pactamycin 415, 423, 426–427 novel sources 59–60 ParM proteins 157 – for drug delivery 54–55 358–360, 453, 456, 457, – inhibiting aaRS 394, 397 460–464, 494–498, 502 – workflow for drug delivery 60–63 patulin 394, 395 1-(1-naphthylmethyl)-piperazine (NMP) 227 PC190723 and 8j 162, 168, 169, 172 NB33 457, 464 p-coumaric acid 170 N-butanoyl-L-homoserine lactone (BHL) 251 penems 100 neamine derivatives 462, 463 -binding protein 2A (PBP2A) 75, 341, 342, 344, 358, 359, 360, 361, 87, 98, 99 373, 374, 377, 380, 418, 455, 456, 460, 461, 2, 3, 13, 53, 57, 59, 73, 75, 78, 462, 494, 496 80–82, 87, 97–99, 184, 204 nicotinamide adenine dinucleotide phosphate pentamidine 342–343 (NADPH) 86 peptide deformylase inhibitors 417–418 nigericin 189, 200, 202 peptidoglycan 133, 134, 137, 139, 143, 145, 75, 83, 140, 141, 142, 145, 188, 190, 146, 183, 185, 187–189, 191, 193, 197, 199, 199, 202 204 nitazoxanide 201 peptidomimetics 198, 202 nitroaromatics 201 center (PTC) 509, 510, 201 513, 515, 516 201 peptidyl transferase inhibitors 361–362 nonribosomal peptides 56 – blasticidin S 358, 361, 362, 471–473, 478, norfloxacin 95, 228 479 novel bacterial type II topoisomerase – peptide bond formation 471–472 inhibitors (NBTIs) 263, 265, 267, 268, – chloramphenicols 220, 223, 228, 361, 373, 272–274, 287–288 374, 378, 379, 471–478, 480, 481 87, 93, 97, 263, 266, 276, – lincosamide action at PTC A-site 472, 473, 277–278, 279–281, 282, 284–285, 287, 527 477, 478 NpmA (m1A1408) 377, 380 – oxazolidinones 471, 473, 476, 477 nucleotide addition cycle (NAC) of RNAP – 471, 473, 481, 482 300, 301, 308 – 358, 361, 362, 471–475, 477, nucleotidyltransferases 85 478, 481, 482 nybomycin 275–276 – sparsomycin 471–473, 478–480 nystatin 418 – 471, 473, 478, 482, 483 permeability behavior 217–219, 224, 228 o phenelfamycins 445 ochratoxin-A 395–396 phenicols 228, 376, 380 octapeptins 224 phenothiazines 228 ofloxacin 95, 186 2-phenylethynesulfonamide 530 137, 138, 139, 187, 188, 191, 193, phenylpropanoids 170 195, 199, 202, 203 PhoQ/PhoP 247, 249, 250 546 Index

phosphatidylglycerol 187, 188, 199 q phosphotransferases 84, 85 QseC/QseB TCS 247, 248 photoactivated localization microscopy quercetin derivatives 286 (PALM) 153 quinazoline 227 phycobilisomes 531 quinazolinediones (diones) 271–272 pifithrin-μ 530 quinoline 226, 227 17, 18 quinoline pyrimidine trione 263, 274–275 plasmid-mediated quinolone resistance quinolones 19, 76, 87, 95, 190, 196, 218, 223, (PMQR) 268 226, 227, 228 platencin 66 – related compounds 267–272 platensimycin 66 quinupristin 473, 482, 483, 515 plectasin 134, 142, 145, 146 quorum sensing (QS) 241–242, 250–253 pleuromutilins 1, 17, 18, 376, 379, 380, 471, 473, 481, 482, 513 r PlsB enzymes 203 65 PlsX/PlsY enzymes 203 ramoplanin 9, 11, 134, 142, 143, 144, 146 10, 92, 221, 222, 224, 229, 230, rapid plasma reagin (RPR) 355–357, 358, 531 361 ponatinib 30 redox enzymes 86 porins 31, 217–222 REP8839 397, 398, 402 porphins 363 resistance 73–74 porphyrins 190, 194, 195, 358, 362, 363 – β-lactam resistome of P. aeruginosa 98 post-transfer editing 391 – – acquired antibiotic resistance in S. aureus post-translocation state (POST) 491–495, 98–100 497, 498, 500 – antibiotic target alteration 86 ppGpp analogs 415, 422 – – chemical modification 88–89 pretransfer editing 391 – – covalent modifications on pretranslocation (PRE) 477, 479, 480, lipopolysaccharide core 92 491–493, 495–498 – – lipopeptide resistance 91–92 proton motive force (PMF) 187–189, 200, – – low-affinity homologous genes 86–88 201 – – ribosomal protection and protoresistance genes 73–74 resistance 89, 91 Pseudomonas quinolone signal (PQS) 251 – – antibiotic transferases 83–86 P-site 412, 414, 417, 419, 423–429 – – hydrolytic enzymes 80, 81–83 pulvomycin 437–442, 444, 446–449 – – redox enzymes 86 purine riboswitches 324, 326, 329, 330, 331 – efflux systems 78, 92–94 puromycin 95, 358, 361, 471–475, 477, 478, – by enzymatic degradation or modification 481, 482 78, 79–80 purpuromycin 394, 397 – – ATP-binding cassette (ABC) superfamily (PZA) 164, 195, 200, 201 94 pyrazoles 281, 283, 286 – – major facilitator superfamily (MSF) pyrazolthiazoles 283 94–96 pyridochromanones 43 – – multidrug and toxic compound extrusion pyridopyrazine 164 (MATE) family 97–98 pyridopyrimidine 227 – – resistance-nodulationdivision (RND) pyridylpyrimidine 171 superfamily 96–97 pyrimidoindoles 266, 281, 283, 284 – – small multidrug-resistance family (SMR) pyrimidothiazine 164 96 pyrithiamine pyrophosphate (PTPP) 328, – horizontal and vertical transmission of 335, 336 resistance genes 74–79 pyrrhocoricin 527, 530 – strategies to overcome 100–101 pyrrolamides 284 resistance and relationship to antibiotic pyrrolopyrimidines 266, 281, 283 consumption 109–110, 121 Index 547 resistance determinants, persistance 456, 460, 461, 462 121–128 riboswitches – genetic mechanisms restoring/improving – as antibacterial drug targets 323–329 fitness 121–126 – c-di-GMP(bis-3-5-cyclic dimeric guanosine – – intra and intergenic compensatory monophosphate) 331–334, 345 mutations 121–125 – FMN 327, 333, 334–335 – – gene duplication, amplification, – lysine 325, 327, 337–339 conversion 126 – purine 324, 326, 329–331 – linked selection and segregation stability – S-adenosylmethionine 326, 327, 339–340 126–127 – thiamine pyrophosphate (TPP) 327, 328, – reacquisition of resistance 127–128 335–336 resistance-nodulation division (RND) ribozymes, as antibacterial drug targets superfamily 96–97 340–344 resistome 73–74 302, 304, 305, 306 473, 481, 482 (KRM-1648) 302, 304, 305 retinoic acid 364, 366, 458 77, 79, 85, 87, 97, 114, 115, 116, retinoids 364, 365, 366 117, 119, 122, 123, 124, 125, 164, 185, 190, retinol 364 194, 202, 300, 301, 302, 305 reutericyclins 190, 192, 194, 195, 202 rifampin 77, 85, 86, 95, 115, 116 reveromycin A 395 14, 15–16, 304, 305, 306 reverse translocation 496, 498 – low-affinity RpoB 87 rhamnolipid 252, 253 302, 304, 305 rhodamine 95 304, 304, 305 rhodanine 159, 167 ripostatin 300, 303, 305, 311 riboflavin 328, 334, 335 RNA polymerase ribonuclease P targeting 355–357 – abortive initiation 299, 300 – aminoglycosides 358, 359–361 – σ subunit 313, 314 – antipsoriatic compounds 364–366 RNA polymerase inhibitors – antisense strategies 357–359 – ansamycins (rifamycins) 302, 304 – macrolides peculiar behavior on bacterial – CBR703 series 300, 301, 302, 305, 309–310 RNase P 363–364 – corallopyronin 300, 303, 305, 311 – peptidyltransferase inhibitors 361–362 – GE23077 300, 303, 305, 314 – substrate masking by synthetic inhibitors – inhibitors as valid source of clinical drugs 363 315 ribosomal exit tunnel 509–510 – SB2 and analogs (phenyl-furanyl-rodanines) – multifunctional tunnel 510–512 313–314 – – binding pocket 512–513 – lasso peptides 308–309 – remotely acquired resistance 513 – lipiarmycin 300, 303, 304, 305, 312–313 – resistance warfare 514–515 – myxopyronin 300, 303, 305, 310–311 – synergism 515–516 – ripostatin 300, 303, 305, 311–312 ribosome biogenesis 371–373 – sorangicin 300, 302, 305–306 – and antibiotics 373–375 – streptolydigin and acyl-tetramic acid family – factors, virulence, and vaccine development antibiotics 307, 308 381–383 – ureidothiophene 303, 305, 315 – methyltransferases 375–380 Ro 13-7410 358, 364, 365 – – integration into ribosome biogenesis roseoflavin 327, 328, 334–335 pathway 380–381 rosiglitazone 253 ribosome recycling factor (RRF) 465 363, 514 ribosome recycling inhibition 501–502 – 50S subunit and GTPase-associated center 503 s – EF-G 503 (S-adenosylmethionine) riboswitches – intersubunit bridge 2a 502 339–340 ribosomes 387, 393 3-sulfogalactolipids 530 548 Index

salicylate 220 thiazolylpeptides 11–13 sanguinarine 159, 160, 162, 165 thioridazine 201, 228 SOS response 35 thiostrepton 413, 415, 418–420, 421, 495, SB-203207 396–398 498–499, 502, 503 SB2 and analogs 303, 305, 313 473, 481, 482 SB-425076 398 66 screening programs and aaRS inhibitors 397 tirandalydigin 308 siamycin I 247, 249 tirandamycin 305, 308 silver nanoparticles 225 85, 99, 100, 185, 358, 359, 360, simocyclinones 263, 265, 267, 284, 286, 287 456, 457, 460, 461, 462 – D8 266, 284–285 topoisomerases (type II) 263–267 small multidrug-resistance family (SMR) 93, – ATPase-domain inhibitors 276 96 – – GyrB and dual-targeting GyrB/ParE 12, 15 ATPase inhibitors 281–284 sorangicin 300–302, 305–307 – chemical structures of inhibitors 265–266 sordarins 501 – DNA-gate inhibitors 267 sparfloxacin 95, 227 – – DNA-gate inhibitors 275–276 sparsomycin 471–473, 478–480 – – NBTIs 272–274 465–466, 492, 495–497 – – quinoline pyrimidine trione 274–275 358, 361–364 – – quinolones and related compounds spirofungin A and B 396 267–272 stambomycins 67 – gyramides 284, 286, 287 streptogramins 10, 374, 376, 378–380, 471, – simocyclinone D8 266, 284–266, 473, 478, 482, 483, 515 285, 286 streptolydigin (Stl) and acyl-tetramic acid totarol 159, 160, 161, 162, 167 family antibiotics 300–302, 305, 307–310 toyocamycin 342, 343, 344 76, 95, 341, 374, 377, 379, 380, translation eukaryotes 500 462, 465, 466, 495, 496 – 40S subunit and decoding site 500 stringent response 393, 401 – 60S subunit and E site 500–501 substrate masking by synthetic inhibitors – eEF2 501 363 translation initiation, in prokaryotes 101, 224 411–414 276 – folate metabolism inhibitors 414–416 sulfonamides 77, 88 – IF2 inhibitors 418–421 sulphonamides 97 – mechanism 411, 412, 413–414 Synercid 10, 515, 516 – methionyl-tRNA formyltransferase inhibitors 417 t – peptide deformylase inhibitors 417–418 taxanes 166–167 – ppGpp analogs 415, 422–423 101, 224 – P-site 412, 414, 417, 419, 423–429 75, 100, 118, 137, 138, 139, 193 translation prokaryotes 137, 138, 139, 183, 187, 190, 191, – 30S subunit decoding site 493–496, 502 193, 195, 197, 198, 199 – 30S head domain 493, 496–497 12, 13, 514, 517, 518 – 50S subunit, GTPase-associated center terahertz (THZ) 228 498–499, 503 terpenoids 56 – EF-G 492–494, 495–500, 501–503 14, 16, 76, 80, 86, 89, 91, 95, 97, – inhibition of protein elongation 494–500 98, 117, 220, 276, 341, 342, 466 – intersubunit bridge 2a 497–498, 502 tetraphenyphosponium 95 – ribosome recycling inhibition 495, TetX enzyme 86 501–503 thermorubin 462, 466 – translocation 453, 454, 465, 466, 480, thiamine pyrophosphate (TPP) riboswitch 491–494 325, 327, 328, 333, 335–336 – – 2a 497, 502, 503 thiazolidione 243 transpeptidation 453, 454 Index 549 triazolopyridine inhibitors 282 v triazolopyridines 281, 282 valinomycin 189, 200 triclosan 203 4, 5, 6, 7, 75, 89, 90, 91, 98, 99, 26, 29, 33, 95, 97, 126, 127 100, 118, 137, 138, 139, 192, 193, 194, 198, 512 199, 202–203, 395, 400, 401 tryptophan 159, 160, 168, 394, 395, 403 vancomycin-resistant enterococci (VRE) 11, tubulin 152, 161, 164, 165, 169, 172 89, 89, 91, 100, 139, 199, 242, 246, 420, 421 tunicamycins 135, 136, 137 viomycin 341, 342, 344, 492, 497–498, 502 two-component systems (TCSs) viriditoxin 162, 164 – case studies as drug targets 243–246 – nonessential systems targeting 246–250 w – as potential anti-infective targets walkmycin B 245, 253 242–243 walrycin 244, 245 363 Watson–Crick base pairings 326, 330 type three secretion system (TTSS) 250, 251 x u XF-73 192, 193, 194, 199 U2585 515, 516 UK-69,753 445 z uracil 479, 480 zantrins 165–166 ureidothiophene 303, 305, 315 Z-ring 152, 153, 154, 155–156, 160, 161, 165, uridyl peptide antibiotics 134, 135 166, 167, 168, 169, 170