Quantification of the Antibacterial Action of Trimethoprim Alone and in Combination with Sulfonamides by Bacterial Growth Kinetics

Seydel, Joachim K.; Wempe, E; Miller, George H.; Miller, Luisa

doi:10.1093/infdis/128.supplement_3.s463

Cited by 17 publications

(8 citation statements)

References 8 publications

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“…In addition, onset of growth suppression was delayed, most likely due to the time required for depletion of an existing CoA pool (14). These findings are similar to those from another class of cofactor biosynthesis inhibitors, the sulfonamides, which inhibit dihydropteroate synthetase, an enzyme involved in biosynthesis of the cofactor folate (43). It can be anticipated that inhibitors of biosynthesis of other cofactors, such as riboflavin and biotin, may show similar microbiological properties.…”

Section: Discussionsupporting

confidence: 57%

Discovery of Inhibitors of 4′-Phosphopantetheine Adenylyltransferase (PPAT) To Validate PPAT as a Target for Antibacterial Therapy

Jonge

Walkup

Lahiri

et al. 2013

Antimicrob Agents Chemother

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Inhibitors of 4=-phosphopantetheine adenylyltransferase (PPAT) were identified through high-throughput screening of the AstraZeneca compound library. One series, cycloalkyl pyrimidines, showed inhibition of PPAT isozymes from several species, with the most potent inhibition of enzymes from Gram-positive species. Mode-of-inhibition studies with Streptococcus pneumoniae and Staphylococcus aureus PPAT demonstrated representatives of this series to be reversible inhibitors competitive with phosphopantetheine and uncompetitive with ATP, binding to the enzyme-ATP complex. The potency of this series was optimized using structure-based design, and inhibition of cell growth of Gram-positive species was achieved. Mode-of-action studies, using generation of resistant mutants with targeted sequencing as well as constructs that overexpress PPAT, demonstrated that growth suppression was due to inhibition of PPAT. An effect on bacterial burden was demonstrated in mouse lung and thigh infection models, but further optimization of dosing requirements and compound properties is needed before these compounds can be considered for progress into clinical development. These studies validated PPAT as a novel target for antibacterial therapy.

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Section: Discussionsupporting

confidence: 57%

Discovery of Inhibitors of 4′-Phosphopantetheine Adenylyltransferase (PPAT) To Validate PPAT as a Target for Antibacterial Therapy

Jonge

Walkup

Lahiri

et al. 2013

Antimicrob Agents Chemother

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show abstract

“…Rather they are related as shown for SA and TMP [Seydel et al, , 1973Seydel and Wempe, 1977, 1978, 1979 in such a man ner that a linear relationship is obtained where k0 is the generation rate constant in the absence of antibacterial drugs, and KA and Kb are constants. KA is a measure of the activity of the particular inhibitor (TMP derivative) tested and C its concentration.…”

Section: Relation Between Concentration and Degree Of Inhibitionmentioning

confidence: 98%

“…In previous papers we have reported on bacterial growth kinetic studies to quantify the synergistic action of trimethoprim/ sulfonamide combinations [Seydel et al, , 1973Seydel and Wempe, 1977, 1978, 1979. The influence of the concentration ratio TMP/SA and of the inhibitory power of the SA derivative on the degreee of syn-1 Supported by the 'Deutsche Forschungsge meinschaft ', Bad Godesberg (FRG). ergism of the combination has been studied.…”

Section: Introductionmentioning

confidence: 99%

Bacterial Growth Kinetics of <i>E. coli</i> in the Presence of Various Trimethoprim Derivatives Alone and in Combination with Sulfonamides

Seydel¹,

Wempe²

1980

Chemotherapy

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Bacterial growth kinetic experiments have been performed to study the potentiating effect of trimethoprim (TMP) and TMP derivatives on the antibacterial action of sulfonamides (SA). The TMP derivatives showed different inhibitory effects when used alone. Derivatives with decreased inhibitory activity excerted ‘bactericidal’ effects only at high concentrations. A rather fast development of bacteria with lower sensitivity against these derivatives has also been observed. In the combined action with SA, however, the same maximal ‘kill’ rate was observed for TMP derivatives as tetroxoprim or derivative IV (table I) at low concentrations of these inhibitors. Under the experimental conditions there is no significant difference between the studied TMP derivatives and various SA in the combined action.

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“…The well-known combination of a sulfonamide (SA) and trimethoprim (TMP) acting sequentially ( fig. 1) on Hr pteroatc syn thetase (PS) and dihydrofolate reductase (DHFR) is a classical example of such a mech anism leading to a synergistic inhibitory effect, especially in gram-negative bacteria [3,13]. Because these drugs penetrate the hydrophobic membrane of mycobacteria only to a limited extent, this combination cannot be used in the treatment of MAC infections.…”

Section: In Vitro Activitiesmentioning

confidence: 99%

Development of Effective Drug Combinations for the Inhibition of Multiply Resistant Mycobacteria, Especially of the <i>Mycobacterium avium </i>Complex

Seydel¹,

Schaper²,

Rüsch-Gerdes³

1992

Chemotherapy

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Rationally designed combinations of rifampicin (RAMP) and thiacetazone plus isonicotinic acid hydrazide and/or ethambutol are highly effective in the treatment of patients (including HIV-positive) infected with multiply resistant mycobacteria of the Mycobacterium avium complex (MAC). Clinical results are very promising. The high efficacy of these combinations is due to the synergistic potentiation of single-drug activities. As soon as rifabutin is marketed, it should replace RAMP in the combination treatment of patients with highly RAMP-resistant MAC bacteria.

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Quantification of the Antibacterial Action of Trimethoprim Alone and in Combination with Sulfonamides by Bacterial Growth Kinetics

Cited by 17 publications

References 8 publications

Discovery of Inhibitors of 4′-Phosphopantetheine Adenylyltransferase (PPAT) To Validate PPAT as a Target for Antibacterial Therapy

Discovery of Inhibitors of 4′-Phosphopantetheine Adenylyltransferase (PPAT) To Validate PPAT as a Target for Antibacterial Therapy

Bacterial Growth Kinetics of <i>E. coli</i> in the Presence of Various Trimethoprim Derivatives Alone and in Combination with Sulfonamides

Development of Effective Drug Combinations for the Inhibition of Multiply Resistant Mycobacteria, Especially of the <i>Mycobacterium avium </i>Complex

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