PMID-sentid	Pub_year	Sent_text	comp_official_name	comp_offset	protein_name	organism	prot_offset
2548057-0	1989	Trimethoprim resistance transposon Tn4003 from Staphylococcus aureus encodes genes for a dihydrofolate reductase and thymidylate synthetase flanked by three copies of IS257.	Trimethoprim	0-12	Dihydrofolate reductase	Staphylococcus aureus	89-112
2548057-5	1989	The central region of the transposon contains the dfrA gene that specifies the S1 dihydrofolate reductase (DHFR) responsible for trimethoprim resistance.	Trimethoprim	129-141	Dihydrofolate reductase	Staphylococcus aureus	82-105
2548057-5	1989	The central region of the transposon contains the dfrA gene that specifies the S1 dihydrofolate reductase (DHFR) responsible for trimethoprim resistance.	Trimethoprim	129-141	Dihydrofolate reductase	Staphylococcus aureus	107-111
2838448-5	1988	Physical studies indicate that Pcr, via a beta-lactamase, and Tpr, via a trimethoprim-insensitive dihydrofolate reductase (DHFR), are also encoded on the pSK1 family by transposons; these transposons have been designated Tn4002 and Tn4003, respectively.	Trimethoprim	73-85	Dihydrofolate reductase	Staphylococcus aureus	123-127
31565920-0	2019	Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin Resistant Staphylococcus aureus.	Trimethoprim	67-79	Dihydrofolate reductase	Staphylococcus aureus	22-45
31565920-0	2019	Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin Resistant Staphylococcus aureus.	Methicillin	133-144	Dihydrofolate reductase	Staphylococcus aureus	22-45
31565920-5	2019	Using biochemical, structural, and computational methods, we are able to optimize these inhibitors to the conserved active sites of the endogenous and trimethoprim resistant DHFR enzymes.	Trimethoprim	151-163	Dihydrofolate reductase	Staphylococcus aureus	174-178
30483998-1	2019	The in vitro and in vivo antimicrobial activities of dihydrofolate reductase (DHFR) inhibitors are inhibited in the presence of free thymidine in the growth milieu and in rodent efficacy models.	Thymidine	133-142	Dihydrofolate reductase	Staphylococcus aureus	53-76
30483998-1	2019	The in vitro and in vivo antimicrobial activities of dihydrofolate reductase (DHFR) inhibitors are inhibited in the presence of free thymidine in the growth milieu and in rodent efficacy models.	Thymidine	133-142	Dihydrofolate reductase	Staphylococcus aureus	78-82
30483998-7	2019	This study confirms that thymidine plays an important antagonistic role when determining the efficacy of DHFR inhibitors in vivo.	Thymidine	25-34	Dihydrofolate reductase	Staphylococcus aureus	105-109
27146708-12	2016	Amongst chosen proteins, rhodomyrtone, both enantiomers, displayed significant potency to dihydrofolate reductase (DHFR) and filamenting temperature-sensitive Z (FtsZ) proteins, compared to their natural substrates/inhibitors.	rhodomyrtone	25-37	Dihydrofolate reductase	Staphylococcus aureus	90-113
27939900-2	2016	The dihydrofolate reductase (DHFR) inhibitor, trimethoprim (TMP), remains one of the most important orally administered antibiotics.	Trimethoprim	46-58	Dihydrofolate reductase	Staphylococcus aureus	4-27
27939900-2	2016	The dihydrofolate reductase (DHFR) inhibitor, trimethoprim (TMP), remains one of the most important orally administered antibiotics.	Trimethoprim	46-58	Dihydrofolate reductase	Staphylococcus aureus	29-33
27939900-2	2016	The dihydrofolate reductase (DHFR) inhibitor, trimethoprim (TMP), remains one of the most important orally administered antibiotics.	Trimethoprim	60-63	Dihydrofolate reductase	Staphylococcus aureus	4-27
27939900-2	2016	The dihydrofolate reductase (DHFR) inhibitor, trimethoprim (TMP), remains one of the most important orally administered antibiotics.	Trimethoprim	60-63	Dihydrofolate reductase	Staphylococcus aureus	29-33
27146708-12	2016	Amongst chosen proteins, rhodomyrtone, both enantiomers, displayed significant potency to dihydrofolate reductase (DHFR) and filamenting temperature-sensitive Z (FtsZ) proteins, compared to their natural substrates/inhibitors.	rhodomyrtone	25-37	Dihydrofolate reductase	Staphylococcus aureus	115-119
27146708-14	2016	This information suggested a cofactor free DHFR and a ligand-unbound FtsZ are likely to prove to be rhodomyrtone targets for MRSA inhibition.	rhodomyrtone	100-112	Dihydrofolate reductase	Staphylococcus aureus	43-47
24428639-0	2014	Structure-based design of new dihydrofolate reductase antibacterial agents: 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines.	7-(benzimidazol-1-yl)-2,4-diaminoquinazolines	76-121	Dihydrofolate reductase	Staphylococcus aureus	30-53
24428639-1	2014	A new series of dihydrofolate reductase (DHFR) inhibitors, the 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for antibacterial potency and enzyme selectivity.	7-(benzimidazol-1-yl)-2,4-diaminoquinazolines	63-108	Dihydrofolate reductase	Staphylococcus aureus	16-39
24428639-1	2014	A new series of dihydrofolate reductase (DHFR) inhibitors, the 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for antibacterial potency and enzyme selectivity.	7-(benzimidazol-1-yl)-2,4-diaminoquinazolines	63-108	Dihydrofolate reductase	Staphylococcus aureus	41-45
24428639-3	2014	Typical of these compounds is 7-((2-thiazol-2-yl)benzimidazol-1-yl)-2,4 diaminoquinazoline, which is a potent inhibitor of S. aureus DHFR (Ki = 0.002 nM) with 46700-fold selectivity over human DHFR.	7-((2-thiazol-2-yl)benzimidazol-1-yl)-2,4 diaminoquinazoline	30-90	Dihydrofolate reductase	Staphylococcus aureus	133-137
19622858-1	2009	Iclaprim is a novel dihydrofolate reductase (DHFR) inhibitor belonging to the 2,4-diaminopyrimidine class of antibiotics, of which trimethoprim (TMP) is the most well known representative.	2,4-diaminopyrimidine	78-99	Dihydrofolate reductase	Staphylococcus aureus	20-43
25087962-0	2014	The Lactone form of stachybotrydial: a new inhibitor of dihydrofolate reductase from stachybotrys sp.	Lactones	4-11	Dihydrofolate reductase	Staphylococcus aureus	56-79
20606069-3	2010	We previously reported phthalazine-based inhibitors of dihydrofolate reductase (DHFR) with potent activity against Bacillus anthracis, a major component of Project BioShield.	phthalazine	23-34	Dihydrofolate reductase	Staphylococcus aureus	55-78
20606069-3	2010	We previously reported phthalazine-based inhibitors of dihydrofolate reductase (DHFR) with potent activity against Bacillus anthracis, a major component of Project BioShield.	phthalazine	23-34	Dihydrofolate reductase	Staphylococcus aureus	80-84
20606069-7	2010	We have determined the cocrystal structure of the wild-type and trimethoprim-resistant (Phe 98 Tyr) DHFR enzyme from S. aureus with RAB1, and we found that rotational freedom of the acryloyl linker region allows the phthalazine moiety to occupy two conformations.	Trimethoprim	64-76	Dihydrofolate reductase	Staphylococcus aureus	100-104
20606069-7	2010	We have determined the cocrystal structure of the wild-type and trimethoprim-resistant (Phe 98 Tyr) DHFR enzyme from S. aureus with RAB1, and we found that rotational freedom of the acryloyl linker region allows the phthalazine moiety to occupy two conformations.	phthalazine	216-227	Dihydrofolate reductase	Staphylococcus aureus	100-104
20026215-0	2010	Towards the understanding of resistance mechanisms in clinically isolated trimethoprim-resistant, methicillin-resistant Staphylococcus aureus dihydrofolate reductase.	Trimethoprim	74-86	Dihydrofolate reductase	Staphylococcus aureus	142-165
20026215-2	2010	Clinically isolated trimethoprim-resistant strains reveal a double mutation, H30N/F98Y, in dihydrofolate reductase (DHFR).	Trimethoprim	20-32	Dihydrofolate reductase	Staphylococcus aureus	91-114
20026215-2	2010	Clinically isolated trimethoprim-resistant strains reveal a double mutation, H30N/F98Y, in dihydrofolate reductase (DHFR).	Trimethoprim	20-32	Dihydrofolate reductase	Staphylococcus aureus	116-120
19280600-0	2009	Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim.	Trimethoprim	139-151	Dihydrofolate reductase	Staphylococcus aureus	51-74
19280600-1	2009	Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites.	NADP	65-70	Dihydrofolate reductase	Staphylococcus aureus	0-23
19280600-1	2009	Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites.	NADP	65-70	Dihydrofolate reductase	Staphylococcus aureus	25-29
19280600-1	2009	Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites.	5,6-dihydrofolate	94-111	Dihydrofolate reductase	Staphylococcus aureus	0-23
19280600-1	2009	Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites.	5,6-dihydrofolate	94-111	Dihydrofolate reductase	Staphylococcus aureus	25-29
19280600-1	2009	Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites.	5,6,7,8-tetrahydrofolic acid	115-139	Dihydrofolate reductase	Staphylococcus aureus	0-23
19280600-1	2009	Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites.	5,6,7,8-tetrahydrofolic acid	115-139	Dihydrofolate reductase	Staphylococcus aureus	25-29
19280600-1	2009	Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites.	Purines	183-190	Dihydrofolate reductase	Staphylococcus aureus	0-23
19280600-1	2009	Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites.	Purines	183-190	Dihydrofolate reductase	Staphylococcus aureus	25-29
19280600-1	2009	Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites.	Methionine	205-215	Dihydrofolate reductase	Staphylococcus aureus	0-23
19280600-1	2009	Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites.	Methionine	205-215	Dihydrofolate reductase	Staphylococcus aureus	25-29
19280600-3	2009	Clinically used compounds targeting DHFR include methotrexate for the treatment of cancer and diaminopyrimidines (DAPs) such as trimethoprim (TMP) for the treatment of bacterial infections.	Methotrexate	49-61	Dihydrofolate reductase	Staphylococcus aureus	36-40
19280600-3	2009	Clinically used compounds targeting DHFR include methotrexate for the treatment of cancer and diaminopyrimidines (DAPs) such as trimethoprim (TMP) for the treatment of bacterial infections.	diaminopyrimidines	94-112	Dihydrofolate reductase	Staphylococcus aureus	36-40
19280600-3	2009	Clinically used compounds targeting DHFR include methotrexate for the treatment of cancer and diaminopyrimidines (DAPs) such as trimethoprim (TMP) for the treatment of bacterial infections.	daps	114-118	Dihydrofolate reductase	Staphylococcus aureus	36-40
19280600-3	2009	Clinically used compounds targeting DHFR include methotrexate for the treatment of cancer and diaminopyrimidines (DAPs) such as trimethoprim (TMP) for the treatment of bacterial infections.	Trimethoprim	128-140	Dihydrofolate reductase	Staphylococcus aureus	36-40
19280600-3	2009	Clinically used compounds targeting DHFR include methotrexate for the treatment of cancer and diaminopyrimidines (DAPs) such as trimethoprim (TMP) for the treatment of bacterial infections.	Trimethoprim	142-145	Dihydrofolate reductase	Staphylococcus aureus	36-40
19280600-4	2009	DAP inhibitors of DHFR have been used clinically for >30 years and resistance to these agents has become widespread.	dap	0-3	Dihydrofolate reductase	Staphylococcus aureus	18-22
19280600-5	2009	Methicillin-resistant Staphylococcus aureus (MRSA), the causative agent of many serious nosocomial and community acquired infections, and other gram-positive organisms can show resistance to DAPs through mutation of the chromosomal gene or acquisition of an alternative DHFR termed "S1 DHFR."	daps	191-195	Dihydrofolate reductase	Staphylococcus aureus	270-274
19280600-5	2009	Methicillin-resistant Staphylococcus aureus (MRSA), the causative agent of many serious nosocomial and community acquired infections, and other gram-positive organisms can show resistance to DAPs through mutation of the chromosomal gene or acquisition of an alternative DHFR termed "S1 DHFR."	daps	191-195	Dihydrofolate reductase	Staphylococcus aureus	286-290
19280600-7	2009	Here, we report the crystal structure of the wild-type chromosomal DHFR from S. aureus in complex with NADPH and TMP.	NADP	103-108	Dihydrofolate reductase	Staphylococcus aureus	67-71
19280600-7	2009	Here, we report the crystal structure of the wild-type chromosomal DHFR from S. aureus in complex with NADPH and TMP.	Trimethoprim	113-116	Dihydrofolate reductase	Staphylococcus aureus	67-71
19280600-8	2009	We have also solved the structure of the exogenous, TMP resistant S1 DHFR, apo and in complex with TMP.	Trimethoprim	52-55	Dihydrofolate reductase	Staphylococcus aureus	69-73
19280600-8	2009	We have also solved the structure of the exogenous, TMP resistant S1 DHFR, apo and in complex with TMP.	Trimethoprim	99-102	Dihydrofolate reductase	Staphylococcus aureus	69-73
22930550-0	2012	Inhibition of bacterial dihydrofolate reductase by 6-alkyl-2,4-diaminopyrimidines.	6-alkyl-2,4-diaminopyrimidines	51-81	Dihydrofolate reductase	Staphylococcus aureus	24-47
22930550-1	2012	(+-)-6-Alkyl-2,4-diaminopyrimidine-based inhibitors of bacterial dihydrofolate reductase (DHFR) have been prepared and evaluated for biological potency against Bacillus anthracis and Staphylococcus aureus.	(+-)-6-alkyl-2,4-diaminopyrimidine	0-34	Dihydrofolate reductase	Staphylococcus aureus	65-88
22930550-1	2012	(+-)-6-Alkyl-2,4-diaminopyrimidine-based inhibitors of bacterial dihydrofolate reductase (DHFR) have been prepared and evaluated for biological potency against Bacillus anthracis and Staphylococcus aureus.	(+-)-6-alkyl-2,4-diaminopyrimidine	0-34	Dihydrofolate reductase	Staphylococcus aureus	90-94
22930550-6	2012	These water molecules are reported to play a critical role in the catalytic reaction, highlighting a new area for inhibitor expansion within the limited architectural variation at the catalytic site of bacterial DHFR.	Water	6-11	Dihydrofolate reductase	Staphylococcus aureus	212-216
22491688-1	2012	Resistance to trimethoprim (TMP) resulting from point mutations in the enzyme drug target dihydrofolate reductase (DHFR) drives the development of new antifolate inhibitors effective against methicillin-resistant Staphylococcus aureus (MRSA).	Trimethoprim	14-26	Dihydrofolate reductase	Staphylococcus aureus	90-113
22491688-1	2012	Resistance to trimethoprim (TMP) resulting from point mutations in the enzyme drug target dihydrofolate reductase (DHFR) drives the development of new antifolate inhibitors effective against methicillin-resistant Staphylococcus aureus (MRSA).	Trimethoprim	14-26	Dihydrofolate reductase	Staphylococcus aureus	115-119
22491688-1	2012	Resistance to trimethoprim (TMP) resulting from point mutations in the enzyme drug target dihydrofolate reductase (DHFR) drives the development of new antifolate inhibitors effective against methicillin-resistant Staphylococcus aureus (MRSA).	Trimethoprim	28-31	Dihydrofolate reductase	Staphylococcus aureus	90-113
22491688-1	2012	Resistance to trimethoprim (TMP) resulting from point mutations in the enzyme drug target dihydrofolate reductase (DHFR) drives the development of new antifolate inhibitors effective against methicillin-resistant Staphylococcus aureus (MRSA).	Trimethoprim	28-31	Dihydrofolate reductase	Staphylococcus aureus	115-119
19622858-1	2009	Iclaprim is a novel dihydrofolate reductase (DHFR) inhibitor belonging to the 2,4-diaminopyrimidine class of antibiotics, of which trimethoprim (TMP) is the most well known representative.	2,4-diaminopyrimidine	78-99	Dihydrofolate reductase	Staphylococcus aureus	45-49
19622858-1	2009	Iclaprim is a novel dihydrofolate reductase (DHFR) inhibitor belonging to the 2,4-diaminopyrimidine class of antibiotics, of which trimethoprim (TMP) is the most well known representative.	Trimethoprim	131-143	Dihydrofolate reductase	Staphylococcus aureus	20-43
19622858-1	2009	Iclaprim is a novel dihydrofolate reductase (DHFR) inhibitor belonging to the 2,4-diaminopyrimidine class of antibiotics, of which trimethoprim (TMP) is the most well known representative.	Trimethoprim	131-143	Dihydrofolate reductase	Staphylococcus aureus	45-49
19622858-1	2009	Iclaprim is a novel dihydrofolate reductase (DHFR) inhibitor belonging to the 2,4-diaminopyrimidine class of antibiotics, of which trimethoprim (TMP) is the most well known representative.	Trimethoprim	145-148	Dihydrofolate reductase	Staphylococcus aureus	20-43
19622858-1	2009	Iclaprim is a novel dihydrofolate reductase (DHFR) inhibitor belonging to the 2,4-diaminopyrimidine class of antibiotics, of which trimethoprim (TMP) is the most well known representative.	Trimethoprim	145-148	Dihydrofolate reductase	Staphylococcus aureus	45-49
19622858-6	2009	The crystal structures of S. aureus DHFR and F98Y mutant DHFR were determined as ternary complexes with NADPH and either AR-101, AR-102 or iclaprim.	NADP	104-109	Dihydrofolate reductase	Staphylococcus aureus	36-40
19622858-6	2009	The crystal structures of S. aureus DHFR and F98Y mutant DHFR were determined as ternary complexes with NADPH and either AR-101, AR-102 or iclaprim.	NADP	104-109	Dihydrofolate reductase	Staphylococcus aureus	57-61
19435963-5	2009	DATA SYNTHESIS: Iclaprim, a novel diaminopyrimidine and DHFR antagonist, has a mechanism of action similar to that of trimethoprim.	iclaprim	16-24	Dihydrofolate reductase	Staphylococcus aureus	56-60
19211577-2	2009	An understanding of the known mechanism of resistance to trimethoprim led to the design of this new inhibitor, with improved affinity towards dihydrofolate reductase (DHFR) from S. aureus and clinically useful activity against S. aureus including isolates resistant to trimethoprim.	Trimethoprim	57-69	Dihydrofolate reductase	Staphylococcus aureus	142-165
19383727-4	2009	Molecular models of S. aureus dihydrofolate reductase (DHFR) were constructed to explore the structural basis of trimethoprim resistance, and to rationalize the observed in vitro fitness of trimethoprim-resistant mutants.	Trimethoprim	113-125	Dihydrofolate reductase	Staphylococcus aureus	30-53
19383727-4	2009	Molecular models of S. aureus dihydrofolate reductase (DHFR) were constructed to explore the structural basis of trimethoprim resistance, and to rationalize the observed in vitro fitness of trimethoprim-resistant mutants.	Trimethoprim	113-125	Dihydrofolate reductase	Staphylococcus aureus	55-59
19383727-4	2009	Molecular models of S. aureus dihydrofolate reductase (DHFR) were constructed to explore the structural basis of trimethoprim resistance, and to rationalize the observed in vitro fitness of trimethoprim-resistant mutants.	Trimethoprim	190-202	Dihydrofolate reductase	Staphylococcus aureus	30-53
19383727-4	2009	Molecular models of S. aureus dihydrofolate reductase (DHFR) were constructed to explore the structural basis of trimethoprim resistance, and to rationalize the observed in vitro fitness of trimethoprim-resistant mutants.	Trimethoprim	190-202	Dihydrofolate reductase	Staphylococcus aureus	55-59
19383727-6	2009	Molecular modelling of mutated DHFR enzymes provided insight into the structural basis of trimethoprim resistance.	Trimethoprim	90-102	Dihydrofolate reductase	Staphylococcus aureus	31-35
19383727-8	2009	CONCLUSIONS: Reduced susceptibility to trimethoprim of DHFR enzymes carrying substitutions L(41)F, F(99)S, F(99)Y and H(150)R appears to result from structural changes that reduce trimethoprim binding to the enzyme.	Trimethoprim	39-51	Dihydrofolate reductase	Staphylococcus aureus	55-59
19383727-8	2009	CONCLUSIONS: Reduced susceptibility to trimethoprim of DHFR enzymes carrying substitutions L(41)F, F(99)S, F(99)Y and H(150)R appears to result from structural changes that reduce trimethoprim binding to the enzyme.	Trimethoprim	180-192	Dihydrofolate reductase	Staphylococcus aureus	55-59
19249312-0	2009	Crystal structures of wild-type and mutant methicillin-resistant Staphylococcus aureus dihydrofolate reductase reveal an alternate conformation of NADPH that may be linked to trimethoprim resistance.	NADP	147-152	Dihydrofolate reductase	Staphylococcus aureus	87-110
19249312-0	2009	Crystal structures of wild-type and mutant methicillin-resistant Staphylococcus aureus dihydrofolate reductase reveal an alternate conformation of NADPH that may be linked to trimethoprim resistance.	Trimethoprim	175-187	Dihydrofolate reductase	Staphylococcus aureus	87-110
19249312-3	2009	However, TMP-resistant strains have arisen with point mutations in dihydrofolate reductase (DHFR), the target for TMP.	Thymidine Monophosphate	9-12	Dihydrofolate reductase	Staphylococcus aureus	67-90
19249312-3	2009	However, TMP-resistant strains have arisen with point mutations in dihydrofolate reductase (DHFR), the target for TMP.	Thymidine Monophosphate	9-12	Dihydrofolate reductase	Staphylococcus aureus	92-96
19249312-3	2009	However, TMP-resistant strains have arisen with point mutations in dihydrofolate reductase (DHFR), the target for TMP.	Thymidine Monophosphate	114-117	Dihydrofolate reductase	Staphylococcus aureus	67-90
19249312-3	2009	However, TMP-resistant strains have arisen with point mutations in dihydrofolate reductase (DHFR), the target for TMP.	Thymidine Monophosphate	114-117	Dihydrofolate reductase	Staphylococcus aureus	92-96
19249312-5	2009	Using a structure-based approach, we have designed a series of novel propargyl-linked DHFR inhibitors that are active against several trimethoprim-resistant enzymes.	Trimethoprim	134-146	Dihydrofolate reductase	Staphylococcus aureus	86-90
19211577-9	2009	However, the increased hydrophobic interactions between iclaprim and DHFR account for increased affinity and, unlike trimethoprim, enable iclaprim to inhibit even the resistant enzyme with nanomolar affinity, thus overcoming the mechanism of trimethoprim resistance.	Trimethoprim	242-254	Dihydrofolate reductase	Staphylococcus aureus	69-73
19211577-2	2009	An understanding of the known mechanism of resistance to trimethoprim led to the design of this new inhibitor, with improved affinity towards dihydrofolate reductase (DHFR) from S. aureus and clinically useful activity against S. aureus including isolates resistant to trimethoprim.	Trimethoprim	57-69	Dihydrofolate reductase	Staphylococcus aureus	167-171
19211577-2	2009	An understanding of the known mechanism of resistance to trimethoprim led to the design of this new inhibitor, with improved affinity towards dihydrofolate reductase (DHFR) from S. aureus and clinically useful activity against S. aureus including isolates resistant to trimethoprim.	Trimethoprim	269-281	Dihydrofolate reductase	Staphylococcus aureus	142-165
19211577-2	2009	An understanding of the known mechanism of resistance to trimethoprim led to the design of this new inhibitor, with improved affinity towards dihydrofolate reductase (DHFR) from S. aureus and clinically useful activity against S. aureus including isolates resistant to trimethoprim.	Trimethoprim	269-281	Dihydrofolate reductase	Staphylococcus aureus	167-171
19211577-9	2009	However, the increased hydrophobic interactions between iclaprim and DHFR account for increased affinity and, unlike trimethoprim, enable iclaprim to inhibit even the resistant enzyme with nanomolar affinity, thus overcoming the mechanism of trimethoprim resistance.	Trimethoprim	117-129	Dihydrofolate reductase	Staphylococcus aureus	69-73
16127079-0	2005	Cloning and characterization of a novel trimethoprim-resistant dihydrofolate reductase from a nosocomial isolate of Staphylococcus aureus CM.S2 (IMCJ1454).	Trimethoprim	40-52	Dihydrofolate reductase	Staphylococcus aureus	63-86
16127079-1	2005	A novel gene, dfrG, encoding a trimethoprim (TMP)-resistant dihydrofolate reductase (DHFR, designated S3DHFR) was cloned from a clinical isolate of methicillin-resistant Staphylococcus aureus.	dfrg	14-18	Dihydrofolate reductase	Staphylococcus aureus	60-83
16127079-1	2005	A novel gene, dfrG, encoding a trimethoprim (TMP)-resistant dihydrofolate reductase (DHFR, designated S3DHFR) was cloned from a clinical isolate of methicillin-resistant Staphylococcus aureus.	dfrg	14-18	Dihydrofolate reductase	Staphylococcus aureus	85-89
16127079-1	2005	A novel gene, dfrG, encoding a trimethoprim (TMP)-resistant dihydrofolate reductase (DHFR, designated S3DHFR) was cloned from a clinical isolate of methicillin-resistant Staphylococcus aureus.	Trimethoprim	31-43	Dihydrofolate reductase	Staphylococcus aureus	60-83
16127079-1	2005	A novel gene, dfrG, encoding a trimethoprim (TMP)-resistant dihydrofolate reductase (DHFR, designated S3DHFR) was cloned from a clinical isolate of methicillin-resistant Staphylococcus aureus.	Trimethoprim	31-43	Dihydrofolate reductase	Staphylococcus aureus	85-89
16127079-1	2005	A novel gene, dfrG, encoding a trimethoprim (TMP)-resistant dihydrofolate reductase (DHFR, designated S3DHFR) was cloned from a clinical isolate of methicillin-resistant Staphylococcus aureus.	Trimethoprim	45-48	Dihydrofolate reductase	Staphylococcus aureus	60-83
16127079-1	2005	A novel gene, dfrG, encoding a trimethoprim (TMP)-resistant dihydrofolate reductase (DHFR, designated S3DHFR) was cloned from a clinical isolate of methicillin-resistant Staphylococcus aureus.	Trimethoprim	45-48	Dihydrofolate reductase	Staphylococcus aureus	85-89
16127079-1	2005	A novel gene, dfrG, encoding a trimethoprim (TMP)-resistant dihydrofolate reductase (DHFR, designated S3DHFR) was cloned from a clinical isolate of methicillin-resistant Staphylococcus aureus.	Methicillin	148-159	Dihydrofolate reductase	Staphylococcus aureus	60-83
16127079-1	2005	A novel gene, dfrG, encoding a trimethoprim (TMP)-resistant dihydrofolate reductase (DHFR, designated S3DHFR) was cloned from a clinical isolate of methicillin-resistant Staphylococcus aureus.	Methicillin	148-159	Dihydrofolate reductase	Staphylococcus aureus	85-89
35439435-4	2022	An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis.	cyclic diadenosine phosphate	57-65	Dihydrofolate reductase	Staphylococcus aureus	132-155
8195827-6	1993	Further milestones in the application of antimicrobial DHFR inhibitors were the introduction of TMP alone in 1972, the launch of a new combination of tetroxoprim, a close TMP-analog, with sulfadiazine, and the successful clinical trials with brodimoprim, which proved clinically efficacious and safe with once-daily low dose monotherapy.	Trimethoprim	96-99	Dihydrofolate reductase	Staphylococcus aureus	55-59
8195827-6	1993	Further milestones in the application of antimicrobial DHFR inhibitors were the introduction of TMP alone in 1972, the launch of a new combination of tetroxoprim, a close TMP-analog, with sulfadiazine, and the successful clinical trials with brodimoprim, which proved clinically efficacious and safe with once-daily low dose monotherapy.	tetroxoprim	150-161	Dihydrofolate reductase	Staphylococcus aureus	55-59
8195827-6	1993	Further milestones in the application of antimicrobial DHFR inhibitors were the introduction of TMP alone in 1972, the launch of a new combination of tetroxoprim, a close TMP-analog, with sulfadiazine, and the successful clinical trials with brodimoprim, which proved clinically efficacious and safe with once-daily low dose monotherapy.	Trimethoprim	171-174	Dihydrofolate reductase	Staphylococcus aureus	55-59
8195827-6	1993	Further milestones in the application of antimicrobial DHFR inhibitors were the introduction of TMP alone in 1972, the launch of a new combination of tetroxoprim, a close TMP-analog, with sulfadiazine, and the successful clinical trials with brodimoprim, which proved clinically efficacious and safe with once-daily low dose monotherapy.	Sulfadiazine	188-200	Dihydrofolate reductase	Staphylococcus aureus	55-59
8195827-6	1993	Further milestones in the application of antimicrobial DHFR inhibitors were the introduction of TMP alone in 1972, the launch of a new combination of tetroxoprim, a close TMP-analog, with sulfadiazine, and the successful clinical trials with brodimoprim, which proved clinically efficacious and safe with once-daily low dose monotherapy.	brodimoprim	242-253	Dihydrofolate reductase	Staphylococcus aureus	55-59
8363365-1	1993	The gene for the trimethoprim-sensitive (Tmps) chromosomal dihydrofolate reductase (DHFR) of Staphylococcus aureus ATCC 25923 was cloned and characterized.	Trimethoprim	17-29	Dihydrofolate reductase	Staphylococcus aureus	59-82
8363365-1	1993	The gene for the trimethoprim-sensitive (Tmps) chromosomal dihydrofolate reductase (DHFR) of Staphylococcus aureus ATCC 25923 was cloned and characterized.	Trimethoprim	17-29	Dihydrofolate reductase	Staphylococcus aureus	84-88
8363365-3	1993	The amino acid sequences of this Tmps DHFR and those of the trimethoprim-resistant type S1 DHFR encoded by transposon Tn4003 are 80% identical.	Trimethoprim	60-72	Dihydrofolate reductase	Staphylococcus aureus	38-42
8363365-4	1993	In contrast to the trimethoprim-resistant enzyme, the Tmps DHFR can be highly overexpressed in Escherichia coli, with most of the recombinant protein occurring in a soluble and an active form.	Trimethoprim	19-31	Dihydrofolate reductase	Staphylococcus aureus	59-63
9054967-0	1997	A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance.	Trimethoprim	93-105	Dihydrofolate reductase	Staphylococcus aureus	58-81
9054967-1	1997	A single amino acid substitution, Phe98 to Tyr98, in dihydrofolate reductase (DHFR) is the molecular origin of trimethoprim (TMP) resistance in Staphylococcus aureus.	Trimethoprim	111-123	Dihydrofolate reductase	Staphylococcus aureus	53-76
9054967-1	1997	A single amino acid substitution, Phe98 to Tyr98, in dihydrofolate reductase (DHFR) is the molecular origin of trimethoprim (TMP) resistance in Staphylococcus aureus.	Trimethoprim	111-123	Dihydrofolate reductase	Staphylococcus aureus	78-82
9054967-1	1997	A single amino acid substitution, Phe98 to Tyr98, in dihydrofolate reductase (DHFR) is the molecular origin of trimethoprim (TMP) resistance in Staphylococcus aureus.	Trimethoprim	125-128	Dihydrofolate reductase	Staphylococcus aureus	53-76
9054967-1	1997	A single amino acid substitution, Phe98 to Tyr98, in dihydrofolate reductase (DHFR) is the molecular origin of trimethoprim (TMP) resistance in Staphylococcus aureus.	Trimethoprim	125-128	Dihydrofolate reductase	Staphylococcus aureus	78-82
9054967-3	1997	In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography.	Trimethoprim	52-55	Dihydrofolate reductase	Staphylococcus aureus	118-122
9054967-3	1997	In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography.	Methotrexate	137-149	Dihydrofolate reductase	Staphylococcus aureus	118-122
9054967-3	1997	In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography.	Methotrexate	137-149	Dihydrofolate reductase	Staphylococcus aureus	126-130
9054967-3	1997	In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography.	Methotrexate	151-154	Dihydrofolate reductase	Staphylococcus aureus	118-122
9054967-3	1997	In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography.	Methotrexate	151-154	Dihydrofolate reductase	Staphylococcus aureus	126-130
9054967-3	1997	In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography.	Trimethoprim	160-163	Dihydrofolate reductase	Staphylococcus aureus	118-122
9054967-3	1997	In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography.	NADP	183-226	Dihydrofolate reductase	Staphylococcus aureus	118-122
9054967-3	1997	In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography.	NADP	228-233	Dihydrofolate reductase	Staphylococcus aureus	118-122
9054967-3	1997	In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography.	Folic Acid	296-302	Dihydrofolate reductase	Staphylococcus aureus	118-122
9054967-3	1997	In order to explore the structural role of Tyr98 in TMP-resistance the ternary complexes of the chromosomal S. aureus DHFR (SaDHFR) with methotrexate (MTX) and TMP in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) as well as that of mutant Phe98Tyr DHFR SaDHFR(F98Y) ternary folate-NADPH complex have been determined by X-ray crystallography.	NADP	303-308	Dihydrofolate reductase	Staphylococcus aureus	118-122
35439435-4	2022	An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis.	cyclic diadenosine phosphate	57-65	Dihydrofolate reductase	Staphylococcus aureus	157-161
35439435-4	2022	An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis.	Folic Acid	179-185	Dihydrofolate reductase	Staphylococcus aureus	132-155
35439435-4	2022	An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis.	Folic Acid	179-185	Dihydrofolate reductase	Staphylococcus aureus	157-161
35439435-4	2022	An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis.	Thymidine	212-221	Dihydrofolate reductase	Staphylococcus aureus	132-155
35439435-4	2022	An initial antibiotic screen in Firmicutes revealed that c-di-AMP production was largely driven by antifolate antibiotics targeting dihydrofolate reductase (DHFR), which promotes folate regeneration required for thymidine biosynthesis.	Thymidine	212-221	Dihydrofolate reductase	Staphylococcus aureus	157-161