Inhibition of recombinant Pneumocystis carinii dihydropteroate synthetase by sulfa drugs

Hong, Yulong; Hossler, Paul A.; Calhoun, David H.; Meshnick, Steve

doi:10.1128/aac.39.8.1756

Cited by 62 publications

(54 citation statements)

References 17 publications

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“…An alternative sulfa drug used against PCP is dapsone (Simonds et al, 1995). SMX and dapsone both act on the folic acid synthesis (FAS) pathway by competing with para-aminobenzoic acid (pABA) in a reaction catalysed by dihydropteroate synthase (DHPS) (Hong et al, 1995). DHPS condenses pABA and dihydropterin pyrophosphate to form the folate precursor, 7,8-dihydropteroate (DHP) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Cloning of the Pneumocystis jirovecii trifunctional FAS gene and complementation of its DHPS activity in Escherichia coli

Iliades

Walker

Castelli

et al. 2004

Fungal Genetics and Biology

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Section: Introductionmentioning

confidence: 99%

Cloning of the Pneumocystis jirovecii trifunctional FAS gene and complementation of its DHPS activity in Escherichia coli

Iliades

Walker

Castelli

et al. 2004

Fungal Genetics and Biology

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“…In the present study we tested the in vitro activities of the antimicrobial drug SMX in combination with the antifungal drugs CAS, AMB, and ITC against 31 clinical Aspergillus isolates obtained from immunocompromised patients with invasive aspergillosis. Our rationale for combining SMX with these drugs was based on three previous findings: (i) SMX alone is moderately active against A. fumigatus in vitro within the concentration range reached in serum in vivo (2); (ii) SMX inhibits folate biosynthesis, a pathway unique for bacteria and fungi alike, and A. fumigatus p-aminobenzoate auxotrophs, blocked in folate biosynthesis, are avirulent in a mouse model of disseminated aspergillosis (5); and (iii) SMX is frequently administered (as SMX-trimethoprim) to immunocompromised patients for PCP prophylaxis (9).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Activity of Caspofungin Combined with Sulfamethoxazole against Clinical Isolates of Aspergillus spp

Yekutiel

Shalit

Shadkchan

et al. 2004

Antimicrob Agents Chemother

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Caspofungin (CAS) inhibits fungal cell wall synthesis. Sulfamethoxazole (SMX) inhibits folate biosynthesis and is active in vitro against Aspergillus spp. We studied the activities of the combination of CAS and SMX against 31 Aspergillus isolates and compared them with that of SMX combined with amphotericin B (AMB) or itraconazole (ITC). MICs and minimal effective concentrations (MECs) were determined by the NCCLS broth microdilution method. With MIC endpoints, the combination of SMX and CAS showed synergy or synergy to additivity against 29 of 31 isolates. With MEC endpoints, synergy to additivity was found against 12 of 31 isolates and indifference was displayed against the rest of them. SMX in combination with AMB or ITC was not truly synergistic, while synergy to additivity was found for SMX-AMB and SMX-ITC against 17 of 31 and 3 of 12 isolates, respectively. No antagonism was found with any of the drug combinations. Further analysis of the synergy of CAS and SMX was performed by detailed measurement of hyphal length by microscopy and time-dependent 2,3-bis(2-methoxy-4-nitro-5-[(sulfenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT)-based hyphal damage experiments. With MEC endpoints, the combination of CAS and SMX was characterized by a greater than 50% decrease in hyphal length compared to the hyphal lengths achieved with double the concentration of each drug alone. The XTT-based hyphal damage studies showed a statistically significant (P < 0.05) reduction in viability with CAS and SMX in combination compared to the viabilities achieved with double the concentration of each drug alone. These findings support the synergy results found by using MIC endpoints and suggest that visual MEC measurements may not be sufficient to identify the synergistic interactions seen by more sensitive, quantitative methods. Animal models are required to validate the significance of the synergy of CAS and SMX against Aspergillus spp. observed in vitro.Invasive aspergillosis is one of the most common invasive fungal infections in immunocompromised patients and carries high mortality rates (10).Current therapeutic agents such as amphotericin B (AMB) and its liposomal formulations, azoles such as itraconazole (ITC) and voriconazole (VRC), and echinocandins such as caspofungin (CAS) are only partially effective for the treatment of this disease; therefore, more effective drugs and drug combinations are needed (8).Sulfamethoxazole (SMX) is an antimicrobial drug which inhibits the biosynthesis of folates (4, 6). SMX is moderately active in vitro against Aspergillus spp. (2), and Aspergillus fumigatus mutants defective in the folate biosynthesis pathway are avirulent (5). SMX is frequently administered in combination with trimethoprim to immunocompromised patients for prophylaxis for Pneumocystis carinii pneumonia (PCP). Interestingly, PCP prophylaxis in AIDS patients is associated with a decreased probability of development of invasive aspergillosis (1).We examined whether the combination of SMX with AMB, ITC, or CAS in vitro exerts ...

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“…49 The mechanism of action of these hybrids differs from the hybrids discussed earlier in this part since the CQ resistance is reversed by GR inhibitors and GSH depletors and not by the presence of calcium channel blockers. The class of dual-function quinolines with resistance-reversing activity has been extended by Sulfonamides are competitive inhibitors of the DHPS enzyme (deoxyhypusine synthase), 54 which catalyses the conversion of para-aminobenzoic acid to dihydropteroate, a fundamental step in folate synthesis. 55 Sulfadoxine is a metabolically stable sulfonamide and can be used for malaria treatment in combination with pyrimethamine.…”

Section: Figure 15mentioning

confidence: 99%

Quinoline-based antimalarial hybrid compounds

Vandekerckhove

D’hooghe

2015

Bioorganic & Medicinal Chemistry

195

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Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the Plasmodium parasite against these drugs and the lack of licensed malaria vaccines have forced chemists to develop synthetic strategies toward novel biologically active molecules. A strategy that has attracted considerable attention in current medicinal chemistry is based on the conjugation of two biologically active molecules into one hybrid compound. Since quinolines are considered to be privileged antimalarial building blocks, the synthesis of quinoline-containing antimalarial hybrids has been elaborated extensively in recent years. This review provides a literature overview of antimalarial hybrid molecules containing a quinoline core, covering publications between 2009 and 2014.

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Inhibition of recombinant Pneumocystis carinii dihydropteroate synthetase by sulfa drugs

Cited by 62 publications

References 17 publications

Cloning of the Pneumocystis jirovecii trifunctional FAS gene and complementation of its DHPS activity in Escherichia coli

Cloning of the Pneumocystis jirovecii trifunctional FAS gene and complementation of its DHPS activity in Escherichia coli

In Vitro Activity of Caspofungin Combined with Sulfamethoxazole against Clinical Isolates of Aspergillus spp

Quinoline-based antimalarial hybrid compounds

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