1. a. Study design schematic Streptococcus mitis (NCTC-2261) Streptococcus mitis (B6) Streptococcus mitis (SK321) Streptococcus mitis (SK564) Streptococcus mitis (SK597) Streptococcus mitis (ATCC-6249) Streptococcus oralis Streptococcus salivarius Streptococcus sanguinis Streptococcus parasanguinis Lactobacillus paracasei (ATCC-27092) Lactobacillus rhamnosus (ATCC-53103) Homo sapiens Streptococcus mutans serotype c (NN2025) Streptococcus gordonii Lactobacillus acidophilus Lactobacillus casei (ATCC-334) Lactobacillus casei (Zhang) Lactobacillus casei (BL23) Lactobacillus salivarius (ATCC-11741) Lactobacillus salivarius (CECT-5713) Lactobacillus salivarius (ACS-116-V-Col5a) Lactobacillus salivarius subsp. salivarius (UCC118) Lactobacillus fermentum (IFO-3956/LMG-18251) Lactobacillus fermentum (ATCC-14931) Lactobacillus fermentum (28-3-CHN) Lactobacillus fermentum (CECT-5716) Bifidobacterium dentium (ATCC-27534) Bifidobacterium longum (strain DJO10A) Veillonella parvula b. phylogenetic profiles target species antitarget species complete proteome sets

2. Examples of modelable S. mutans virulence factors Examples of modelable and druggable S. mutans proteins druggable mutltiple sugar binding protein zDOPE (model reliability) = -1.57 drugEBIlity score = 0.76 not druggable proton/lactate pump zDOPE (model reliability) = -1.73 drugEBIlity score = -0.71 favorable profile unknown enzyme resolution = 2.38 Å drugEBIlity score = 0.57 comparative model nonhydrolyzing UDP acetyl- glucosamine epimerase zDOPE (model reliability) = -1.75 drugEBIlity score = 0.82 crystal structure glucosamine-6-PO 4 deaminase resolution = 2.03 Å drugEBIlity score = 0.77 druggable and favorable profile major cell-surface adhesin zDOPE (model reliability) = -1.50 drugEBIlity score = 0.41 a. b. c. d. e. f.

3. multiple sugar-binding MS transport ATP-binding ATP-binding transporter fructose phosphotransferase IIABC fructose phosphotransferase IIBC fructose phosphotransferase IIA isocitrate dehydrogenase acetylornithine aminotransferase purine nucleoside phosphorylase glycogen synthase Glu1-PO4 adenylyltransferase beta-glucosidase endoglucanase lactate dehydrogenase phosphocarrier protein HPr PEP-phosphotransferase proton/lactic acid pump lactose-specific PO4-transferase N'N' DCHC-sensitive ATPase signal recognition particle formyltetrahydrofolate ligase panthothenate flavoprotein malolactic fermentation reg DNA-dir RNA polymerase glycogen phosphorylase phosphorylase sucrose phosphorylase GTF-I 1,3α-branch glucosyltransferase-SI glucosyltransferase-S 1,4α-glucan branching dextran glucosidase glucan-binding protein A secr peptidoglycan hydrolase glucan-binding protein C BglB-like Gbp with lipase GbpC response regulator major cell-surface adhesin cell surface antigen I/II collagen-binding adhesin amylase-binding protein A amylase-binding protein B ATP-binding transporter competence histidine kinase competence transcriptional reg biofilm regulatory protein A response regulator of BrpA-1 response regulator of BrpA-2 lantibiotic mutacin II lantibiotic mutacin 1140 lantibiotic mutacin M lantibiotic mutacin B-Ny266 bacteriocin SmbA bacteriocin secretion protein bacteriocin peptide undecaprenol kinase rRNA maturation factor mutacin 1140 modifying enzyme serine-threonine kinase PknB oxidative stress sensor kinase collagenase metabolismattachmentcoordination proteins by functional similarity sugar uptake nutrient uptake energy storage acid production acid tolerance S. mutans virulence factors glucan production glucan attachment other attach quorum sensing lantibiotics lantibiotic regulation H. sapiens L. rhamnosus (ATCC-53103) L. paracasei (ATCC-27092) S. parasanguinis S. sanguinis S. salivarius S. oralis S. mitis (ATCC-6249) S. mitis (SK597) S. mitis (SK564) S. mitis (SK321) S. mitis (B6) S. mitis (NCTC-2261) phylogenetic profiles protein similarity (matching HMM columns / length of protein) target proteomes antitarget proteomes V. parvula B. longum (strain DJO10A) B. dentium (ATCC-27534) L. fermentum (CECT-5716) L. fermentum (28-3-CHN) L. fermentum (ATCC-14931) L. fermentum (IFO-3956/LMG-18251) L. salivarius subsp. salivarius (UCC118) L. salivarius (ACS-116-V-Col5a) L. salivarius (CECT-5713) L. salivarius (ATCC-11741) L. casei (BL23) L. casei (Zhang) L.casei (ATCC-334) L. acidophilus S. gordonii S. mutans serotype c (NN2025) modelable druggable tractability Q00749 Q00752 P72477 Q8DUN3 Q8DWE7 Q8DWE6 Q59940 Q59928 Q8DTU4 Q8CWX0 Q8DT53 Q8DUE7 Q8CVC4 P26283 P45596 P45595 P50976 P26426 P95783 Q54431 Q59925 Q8DU74 Q8DWC9 Q8DWG2 Q8DT55 Q8DT31 P10249 P08987 P13470 P49331 Q8DT52 Q99040 Q8DRV2 Q8DWM3 Q8DTF1 Q8DUW9 Q9S151 P11657 P23504 Q76H84 A8AZZ3 A8AUM3 Q8DW05 Q8DS94 Q8DS39 Q8DVR0 Q8DVJ9 Q8DVJ8 O54329 O68586 Q7BV70 P80666 Q5TLL1 Q8DSA3 Q8CVC8 Q05888 Q8DSY7 O68588 Q8DVK1 Q8DT64 Q8DUX4

4. phylogenetic profiles Adhesin A3VP1 of AntigenI/II Glucosamine-6-phosphate deaminase Mn-dependent inorganic pyrophosphatase Unknown function 1377c Isopropylmalate dehydratase V-region of antigen I/II Phosphatase/hydrolase Phosphatase NADP-dependent GAPDH Unknown enzyme Dihydroorotate dehydrogenase Dextran glucosidase Peptide chain release factor Tagatose 1,6-aldolase Carboxymuconolactone decarboxylase protein similarity (matching HMM columns / length of protein) target proteomes antitarget proteomes S. mutans PDBs druggable tractability 3IOX 2RI1 1I74 3L7V 2HCU 1JMM 3L7Y 1WVI 2QE0 3IJT 3OIX 2ZID 2ZIC 1ZBT 3IV3 3LVY H. sapiens L. rhamnosus (ATCC-53103) L. paracasei (ATCC-27092) S. parasanguinis S. sanguinis S. salivarius S. oralis S. mitis (ATCC-6249) S. mitis (SK597) S. mitis (SK564) S. mitis (SK321) S. mitis (B6) S. mitis (NCTC-2261) UDP acetylglucosamine epimerase Phosphorylase Trans enoyl ACP reductase Oligopeptide ABC transporter Anthranilate phosphoribosyltransferase Periplasmic ferrichrome ABC transporter UDP acetylglucosamine carboxyvinyltransferase 1 UDP acetylglucosamine carboxyvinyltransferase 2 Adenylate kinase D-alanine polyligase dTDP-glucose dehydratase Dihydroorotate dehydrogenase Secreted translocase β-galactosidase Imidazole carboxamide isomerase Acetoin dehydrogenase Bifunctional protein glmU Methionyl-tRNA synthetase Guanylate kinase Glycerol dehydrogenase Phosphatase α-acetolactate synthase Thiazole pyrodixine kinase Glutamyl-tRNA amidotransferase subA Bisphosphoglycerate mutase Manganese inorganic pyrophosphatase Surface protein I/II Response regulator AdcA-like Zn adhesin lipoprotein Acetyltransferase DNA polymerase Imidazole glycerol-PO4 synthase SAM methyltransferase Glucanotransferase tRNA thiouridylase 30S ribosomal protein Dihydrodipicolinate synthase Pyrimidine-nucleoside phosphorylase Orotidine 5'-phosphate decarboxylase Unknown hydrolase/phosphatase Maltose operon transcriptional repressor Uracil phosphoribosyltransferase ATP synthase Lactose phosphotransferase repressor Catabolite control protein ATP synthase Malolactic enzyme LytTr DNA-binding Purine operon repressor Tryptophan synthase tRNA YrdC-modifier Isopropylmalate dehydratase Adenine phosphoribosyltransferase Deoxycytidylate deaminase RNA-diphosphate reductase Adenylate kinase Glycosyltransferase Anaerobic RNA-triphosphate reductase ATP-binding ABC transporter dTDP keto rhamnose reductase ATP-binding ABC transporter DTDP keto rhamnose reductase Homoserine succinyltransferase Carbamoyl-phosphate synthase NADP-dependent GAPDH Unique & uncharacterized Tellurite resistance protein Ferrous ion transport protein Phosphopentomutase Transcription regulator Chorismate mutase Phosphofructokinase Cysteine synthase Glucan glucosidase Histidine kinase Citrate synthase Dextran glucosidase Unknown hydrolase/phosphatase Tagatose diphosphate aldolase Amino acid aminotransferase Uracil-DNA glycosylase DNA damage sensor ATP synthase V. parvula B. longum (strain DJO10A) B. dentium (ATCC-27534) L. fermentum (CECT-5716) L. fermentum (28-3-CHN) L. fermentum (ATCC-14931) L. fermentum (IFO-3956/LMG-18251) L. salivarius subsp. salivarius (UCC118) L. salivarius (ACS-116-V-Col5a) L. salivarius (CECT-5713) L. salivarius (ATCC-11741) L. casei (BL23) L. casei (Zhang) L. casei (ATCC-334) L. acidophilus S. gordonii S. mutans serotype c (NN2025) Q8DTB7 Q8DT31 Q8DSN4 Q8DW25 Q8DVF6 Q8DUD7 Q8DT57 Q8DT24 Q8DS33 Q53526 P95780 Q8DTV0 Q8DSJ6 P50978 Q8DTR2 Q8DTL3 Q8DSX2 Q8DSW8 Q8DVK6 Q8DVJ3 Q8DV60 Q8DTA6 Q8DSS7 Q8DSG5 P59161 O68579 Q9RFI8 Q8DVJ8 Q8DTN1 Q8DSV5 Q8DWN8 Q8DTR3 Q8DTH5 Q8DT30 Q8DRS4 Q8DWB3 Q8DUE5 Q8DU33 Q8DTV1 Q8DTS3 Q8DT29 Q8DST6 P95789 P26422 O07329 A6PY32 Q8DWC7 Q8DVZ8 Q8DVV6 Q8DVF3 Q8DTG7 Q8DTG5 Q8DT95 Q8DSE5 Q8DV42 Q8DTS0 Q8DSH9 Q8DRY2 Q8DW32 Q8DUS5 Q8DTZ7 O33664 Q8DT96 Q8DUP4 Q59931 Q8DTQ1 Q8DSW3 Q8DVC3 Q8DTU0 Q8DTZ5 Q8DTP2 Q8KWU0 Q8DVJ2 Q99040 Q8DT45 Q59939 Q2HWU5 Q8DV06 Q8DUY6 P26425 Q8DWM1 Q8DTV8 Q8DTC4 P95790 S. mutans proteins modelable druggable a. b.

5. -1.57 0.76 -1.02 0.27 -1.25 0.52 -0.30 -0.08 -0.88 0.36 -1.01 0.74 -0.71 0.80 -0.93 -0.85 -0.44 0.36 0.76 0.78 -1.23 -0.15 -1.73 -0.71 -0.85 -0.75 -1.25 0.80 -0.96 0.79 -0.85 0.74 -1.18 0.82 -1.12 0.82 -0.45 -0.70 -0.15 0.39 -0.09 0.80 -0.25 0.77 -1.77 0.55 -0.69 0.77 -1.08 -0.71 -1.59 0.78 -1.50 0.41 -0.37 0.77 -1.88 0.77 0.72 0.81 0.60 -0.97 0.14 -0.41 0.97 0.81 0.86 0.80 0.76 -0.08 0.52 0.80 -0.34 0.80 0.19 0.80 -1.05 0.77 figure 3 -1.75 0.82 -1.12 0.82 -1.01 0.82 -1.13 0.81 -1.33 0.81 -1.46 0.81 -1.10 0.81 -1.18 0.81 -1.44 0.81 -1.04 0.81 -1.82 0.81 -1.35 0.80 -1.23 0.80 -1.87 0.80 -1.14 0.79 -1.04 0.79 -1.03 0.79 -1.09 0.79 -1.36 0.78 -1.20 0.78 -1.38 0.78 -1.24 0.78 -1.27 0.78 -1.13 0.78 -1.20 0.78 -1.50 0.78 -1.17 0.77 -1.88 0.77 -1.37 0.77 -1.23 0.77 -1.36 0.76 -1.47 0.76 -1.41 0.76 -1.08 0.76 -1.20 0.76 -1.71 0.75 -1.63 0.75 -1.07 0.75 -1.45 0.75 -1.82 0.75 -1.63 0.75 -1.39 0.75 -1.14 0.75 -2.20 0.75 -1.11 0.75 -1.47 0.75 -1.14 0.74 -1.12 0.74 -1.22 0.74 -1.06 0.74 -1.63 0.74 -2.10 0.74 -1.30 0.74 -1.19 0.74 -1.15 0.73 -1.10 0.73 -1.13 0.73 -1.08 0.73 -1.14 0.72 -1.58 0.72 -1.19 0.72 -1.39 0.72 -1.32 0.71 -1.30 0.70 -1.40 0.70 -1.41 0.69 -1.30 0.68 -1.95 0.66 -1.90 0.63 -1.43 0.58 -1.13 0.58 -1.13 0.57 -1.17 0.56 -1.77 0.55 -1.30 0.55 -1.35 0.55 -1.74 0.55 -1.59 0.54 -1.18 0.54 -1.94 0.54 -1.25 0.53 -1.53 0.53 -1.52 0.52 -1.42 0.51 figure 4b 0.77 0.74 0.71 0.70 0.66 0.57 0.56 0.54 0.53 figure 4a

6. virulence factors 61, literature review structures 81, PDB proteome 2391, UniProt comparative modeling 616 of 1631, MODELLER active site analysis 110, drugEBIlity phylogenetic profiles 110, HHsearch unique common rare

7. metabolismattachmentcoordination proteins by functional similarity sugar uptake nutrient uptake energy storage acid production acid tolerance S. mutans virulence factors glucan production glucan attachment other attach quorum sensing lantibiotics lantibiotic regulation H. sapiens L. rhamnosus (ATCC-53103) L. paracasei (ATCC-27092) S. parasanguinis S. sanguinis S. salivarius S. oralis S. mitis (ATCC-6249) S. mitis (SK597) S. mitis (SK564) S. mitis (SK321) S. mitis (B6) S. mitis (NCTC-2261) phylogenetic profiles protein similarity (matching HMM columns / length of protein) target proteomes antitarget proteomes V. parvula B. longum (strain DJO10A) B. dentium (ATCC-27534) L. fermentum (CECT-5716) L. fermentum (28-3-CHN) L. fermentum (ATCC-14931) L. fermentum (IFO-3956/LMG-18251) L. salivarius subsp. salivarius (UCC118) L. salivarius (ACS-116-V-Col5a) L. salivarius (CECT-5713) L. salivarius (ATCC-11741) L. casei (BL23) L. casei (Zhang) L.casei (ATCC-334) L. acidophilus S. gordonii S. mutans serotype c (NN2025) modelable druggable tractability multiple sugar-binding MS transport ATP-binding ATP-binding transporter fructose phosphotransferase IIABC fructose phosphotransferase IIBC fructose phosphotransferase IIA isocitrate dehydrogenase acetylornithine aminotransferase purine nucleoside phosphorylase glycogen synthase Glu1-PO4 adenylyltransferase beta-glucosidase endoglucanase lactate dehydrogenase phosphocarrier protein HPr PEP-phosphotransferase proton/lactic acid pump lactose-specific PO4-transferase N'N' DCHC-sensitive ATPase signal recognition particle formyltetrahydrofolate ligase panthothenate flavoprotein malolactic fermentation reg DNA-dir RNA polymerase glycogen phosphorylase phosphorylase sucrose phosphorylase GTF-I 1,3α-branch glucosyltransferase-SI glucosyltransferase-S 1,4α-glucan branching dextran glucosidase glucan-binding protein A secr peptidoglycan hydrolase glucan-binding protein C BglB-like Gbp with lipase GbpC response regulator major cell-surface adhesin cell surface antigen I/II collagen-binding adhesin amylase-binding protein A amylase-binding protein B ATP-binding transporter competence histidine kinase competence transcriptional reg biofilm regulatory protein A response regulator of BrpA-1 response regulator of BrpA-2 lantibiotic mutacin II lantibiotic mutacin 1140 lantibiotic mutacin M lantibiotic mutacin B-Ny266 bacteriocin SmbA bacteriocin secretion protein bacteriocin peptide undecaprenol kinase rRNA maturation factor mutacin 1140 modifying enzyme serine-threonine kinase PknB oxidative stress sensor kinase collagenase Q00749 Q00752 P72477 Q8DUN3 Q8DWE7 Q8DWE6 Q59940 Q59928 Q8DTU4 Q8CWX0 Q8DT53 Q8DUE7 Q8CVC4 P26283 P45596 P45595 P50976 P26426 P95783 Q54431 Q59925 Q8DU74 Q8DWC9 Q8DWG2 Q8DT55 Q8DT31 P10249 P08987 P13470 P49331 Q8DT52 Q99040 Q8DRV2 Q8DWM3 Q8DTF1 Q8DUW9 Q9S151 P11657 P23504 Q76H84 A8AZZ3 A8AUM3 Q8DW05 Q8DS94 Q8DS39 Q8DVR0 Q8DVJ9 Q8DVJ8 O54329 O68586 Q7BV70 P80666 Q5TLL1 Q8DSA3 Q8CVC8 Q05888 Q8DSY7 O68588 Q8DVK1 Q8DT64 Q8DUX4

8. phylogenetic profiles Adhesin A3VP1 of AntigenI/II Glucosamine-6-phosphate deaminase Mn-dependent inorganic pyrophosphatase Unknown function 1377c Isopropylmalate dehydratase V-region of antigen I/II Phosphatase/hydrolase Phosphatase NADP-dependent GAPDH Unknown enzyme Dihydroorotate dehydrogenase Dextran glucosidase Peptide chain release factor Tagatose 1,6-aldolase Carboxymuconolactone decarboxylase protein similarity (matching HMM columns / length of protein) target proteomes antitarget proteomes S. mutans PDBs druggable tractability 3IOX 2RI1 1I74 3L7V 2HCU 1JMM 3L7Y 1WVI 2QE0 3IJT 3OIX 2ZID 2ZIC 1ZBT 3IV3 3LVY H. sapiens L. rhamnosus (ATCC-53103) L. paracasei (ATCC-27092) S. parasanguinis S. sanguinis S. salivarius S. oralis S. mitis (ATCC-6249) S. mitis (SK597) S. mitis (SK564) S. mitis (SK321) S. mitis (B6) S. mitis (NCTC-2261) UDP acetylglucosamine epimerase Phosphorylase Trans enoyl ACP reductase Oligopeptide ABC transporter Anthranilate phosphoribosyltransferase Periplasmic ferrichrome ABC transporter UDP acetylglucosamine carboxyvinyltransferase 1 UDP acetylglucosamine carboxyvinyltransferase 2 Adenylate kinase D-alanine polyligase dTDP-glucose dehydratase Dihydroorotate dehydrogenase Secreted translocase β-galactosidase Imidazole carboxamide isomerase Acetoin dehydrogenase Bifunctional protein glmU Methionyl-tRNA synthetase Guanylate kinase Glycerol dehydrogenase Phosphatase α-acetolactate synthase Thiazole pyrodixine kinase Glutamyl-tRNA amidotransferase subA Bisphosphoglycerate mutase Manganese inorganic pyrophosphatase Surface protein I/II Response regulator AdcA-like Zn adhesin lipoprotein Acetyltransferase DNA polymerase Imidazole glycerol-PO4 synthase SAM methyltransferase Glucanotransferase tRNA thiouridylase 30S ribosomal protein Dihydrodipicolinate synthase Pyrimidine-nucleoside phosphorylase Orotidine 5'-phosphate decarboxylase Unknown hydrolase/phosphatase Maltose operon transcriptional repressor Uracil phosphoribosyltransferase ATP synthase Lactose phosphotransferase repressor Catabolite control protein ATP synthase Malolactic enzyme LytTr DNA-binding Purine operon repressor Tryptophan synthase tRNA YrdC-modifier Isopropylmalate dehydratase Adenine phosphoribosyltransferase Deoxycytidylate deaminase RNA-diphosphate reductase Adenylate kinase Glycosyltransferase Anaerobic RNA-triphosphate reductase ATP-binding ABC transporter dTDP keto rhamnose reductase ATP-binding ABC transporter DTDP keto rhamnose reductase Homoserine succinyltransferase Carbamoyl-phosphate synthase NADP-dependent GAPDH Unique & uncharacterized Tellurite resistance protein Ferrous ion transport protein Phosphopentomutase Transcription regulator Chorismate mutase Phosphofructokinase Cysteine synthase Glucan glucosidase Histidine kinase Citrate synthase Dextran glucosidase Unknown hydrolase/phosphatase Tagatose diphosphate aldolase Amino acid aminotransferase Uracil-DNA glycosylase DNA damage sensor ATP synthase V. parvula B. longum (strain DJO10A) B. dentium (ATCC-27534) L. fermentum (CECT-5716) L. fermentum (28-3-CHN) L. fermentum (ATCC-14931) L. fermentum (IFO-3956/LMG-18251) L. salivarius subsp. salivarius (UCC118) L. salivarius (ACS-116-V-Col5a) L. salivarius (CECT-5713) L. salivarius (ATCC-11741) L. casei (BL23) L. casei (Zhang) L. casei (ATCC-334) L. acidophilus S. gordonii S. mutans serotype c (NN2025) Q8DTB7 Q8DT31 Q8DSN4 Q8DW25 Q8DVF6 Q8DUD7 Q8DT57 Q8DT24 Q8DS33 Q53526 P95780 Q8DTV0 Q8DSJ6 P50978 Q8DTR2 Q8DTL3 Q8DSX2 Q8DSW8 Q8DVK6 Q8DVJ3 Q8DV60 Q8DTA6 Q8DSS7 Q8DSG5 P59161 O68579 Q9RFI8 Q8DVJ8 Q8DTN1 Q8DSV5 Q8DWN8 Q8DTR3 Q8DTH5 Q8DT30 Q8DRS4 Q8DWB3 Q8DUE5 Q8DU33 Q8DTV1 Q8DTS3 Q8DT29 Q8DST6 P95789 P26422 O07329 A6PY32 Q8DWC7 Q8DVZ8 Q8DVV6 Q8DVF3 Q8DTG7 Q8DTG5 Q8DT95 Q8DSE5 Q8DV42 Q8DTS0 Q8DSH9 Q8DRY2 Q8DW32 Q8DUS5 Q8DTZ7 O33664 Q8DT96 Q8DUP4 Q59931 Q8DTQ1 Q8DSW3 Q8DVC3 Q8DTU0 Q8DTZ5 Q8DTP2 Q8KWU0 Q8DVJ2 Q99040 Q8DT45 Q59939 Q2HWU5 Q8DV06 Q8DUY6 P26425 Q8DWM1 Q8DTV8 Q8DTC4 P95790 S. mutans proteins modelable druggable a. b.