Ácido nalidíxico

• El ácido nalidíxico inhibe la ADN girasa bacteriana (topoisomerasa II), evitando la replicación y transcripción del ADN.
• Interfiere con la superenrollamiento del ADN, lo que lleva a la muerte celular.
• Los objetivos moleculares del compuesto son las topoisomerasas bacterianas .

Clinical Applications

1.1 Treatment of Urinary Tract Infections

Nalidixic acid is primarily used for treating urinary tract infections (UTIs) caused by susceptible gram-negative microorganisms. It is particularly effective against Escherichia coli, Enterobacter species, and Proteus species. The drug operates effectively across a wide urinary pH range, making it suitable for various patient populations .

1.2 Systemic Infections

In addition to UTIs, nalidixic acid has been administered intravenously for systemic infections, especially those involving the urinary tract . Its bactericidal properties are most potent at concentrations between 50 to 200 µg/ml, effectively inhibiting DNA synthesis in bacteria .

Resistance Patterns

3.1 Emergence of Resistance

Resistance to nalidixic acid has been documented among various bacterial strains. A study indicated that approximately 38.5% of isolated strains from blood samples showed resistance to nalidixic acid . This resistance is concerning as it reflects broader trends in antibiotic resistance among hospital-associated organisms.

3.2 Monitoring Resistance

Monitoring nalidixic acid susceptibility is crucial in understanding resistance patterns to other antibiotics like ciprofloxacin. In regions such as the Indian Subcontinent, nalidixic acid susceptibility testing has served as an effective method for tracking ciprofloxacin resistance among Salmonella strains .

Case Studies and Research Findings

4.1 Clinical Case Reports

A notable case reported transient hyperglycemia and glycosuria following an overdose of nalidixic acid, highlighting potential side effects that clinicians should monitor during treatment .

4.2 Synergistic Effects with Other Antibiotics

Recent research has explored the synergistic effects of nalidixic acid when combined with tetracycline against multi-drug resistant strains of Acinetobacter baumannii and E. coli. This combination demonstrated enhanced efficacy in both in vitro and in vivo models, suggesting potential therapeutic strategies to combat resistant infections .

Data Tables

Biochemical Properties

Nalidixic acid plays a crucial role in biochemical reactions by targeting bacterial DNA gyrase and topoisomerase IV, enzymes essential for DNA replication and transcription. By inhibiting these enzymes, nalidixic acid prevents the supercoiling and uncoiling of bacterial DNA, thereby halting DNA synthesis. This interaction is specific to bacterial enzymes, making nalidixic acid effective against bacterial infections while having minimal impact on human cells .

Cellular Effects

Nalidixic acid exerts significant effects on various types of cells, particularly bacterial cells. It disrupts cell function by inhibiting DNA synthesis, leading to cell death. In bacterial cells, nalidixic acid affects cell signaling pathways, gene expression, and cellular metabolism. The inhibition of DNA gyrase and topoisomerase IV results in the accumulation of DNA breaks, which triggers the bacterial SOS response and ultimately leads to cell death .

Molecular Mechanism

The molecular mechanism of nalidixic acid involves its binding to the A subunit of DNA gyrase and the C subunit of topoisomerase IV. This binding interferes with the enzymes’ ability to introduce negative supercoils into DNA, which is essential for DNA replication and transcription. By stabilizing the DNA-enzyme complex, nalidixic acid prevents the re-ligation of DNA strands, leading to the accumulation of DNA breaks and inhibition of bacterial growth .

Temporal Effects in Laboratory Settings

In laboratory settings, the effects of nalidixic acid change over time. Initially, nalidixic acid rapidly inhibits DNA synthesis, leading to a decrease in bacterial growth. Over time, the stability and degradation of nalidixic acid can influence its effectiveness. Studies have shown that nalidixic acid is relatively stable under laboratory conditions, but prolonged exposure can lead to the development of bacterial resistance .

Dosage Effects in Animal Models

The effects of nalidixic acid vary with different dosages in animal models. At therapeutic doses, nalidixic acid effectively treats bacterial infections without causing significant toxicity. At high doses, nalidixic acid can exhibit toxic effects, including gastrointestinal disturbances and central nervous system toxicity. Threshold effects have been observed, where increasing the dosage beyond a certain point does not significantly enhance its antibacterial activity but increases the risk of adverse effects .

Metabolic Pathways

Nalidixic acid is metabolized in the liver, primarily through hydroxylation to form hydroxynalidixic acid. This metabolite retains antibacterial activity and contributes to the overall effectiveness of nalidixic acid. The metabolic pathways involve enzymes such as cytochrome P450, which facilitate the conversion of nalidixic acid to its active metabolite. The presence of hydroxynalidixic acid in the bloodstream ensures sustained antibacterial activity .

Transport and Distribution

Nalidixic acid is transported and distributed within cells and tissues through passive diffusion. It can cross cell membranes and accumulate in bacterial cells, where it exerts its antibacterial effects. The distribution of nalidixic acid within tissues is influenced by factors such as blood flow and tissue permeability. Transporters and binding proteins may also play a role in the cellular uptake and distribution of nalidixic acid .

Subcellular Localization

Nalidixic acid primarily localizes in the cytoplasm of bacterial cells, where it interacts with DNA gyrase and topoisomerase IV. The subcellular localization of nalidixic acid is crucial for its antibacterial activity, as it needs to reach its target enzymes to inhibit DNA synthesis. Post-translational modifications and targeting signals may influence the localization and activity of nalidixic acid within bacterial cells .

• El ácido nalidíxico se sintetiza a partir de 2-metilpiridina para formar 2-amino-5-metilpiridina.
• El último compuesto se condensa luego con formiato de etilo y oxalato de dietilo para producir N-(2-metil-5-amino-piridina)metilen malonato.
• La ciclación a 260-270 °C seguida de hidrólisis con hidróxido de sodio produce ácido 7-metil-1,8-naftiridina-4-hidroxi-3-carboxílico.
• Finalmente, la N-alquilación con bromoetano conduce al ácido nalidíxico .

• El ácido nalidíxico exhibe actividad antibacteriana contra bacterias gramnegativas y algunas grampositivas.
• Actúa bacteriostáticamente a concentraciones más bajas y bactericidamente a concentraciones más altas.
• Las reacciones comunes incluyen hidrólisis, alquilación y oxidación.
• Los principales productos formados incluyen ácido 7-metil-1,8-naftiridina-4-hidroxi-3-carboxílico y sus derivados .

• El ácido nalidíxico es único debido a su estructura de naftiridona.
• Compuestos similares incluyen otras quinolonas como ciprofloxacina, levofloxacina y moxifloxacina .

Nalidixic acid, a synthetic antibacterial agent belonging to the quinolone class, was first introduced in the 1960s. It primarily exhibits activity against gram-negative bacteria, making it a critical compound in the treatment of urinary tract infections and other bacterial infections. This article explores its biological activity, mechanisms of action, and relevant case studies, providing a comprehensive overview of its role in antibacterial therapy.

Nalidixic acid acts primarily by inhibiting bacterial DNA synthesis. It targets the enzyme DNA gyrase, which is crucial for DNA replication and transcription in bacteria. The inhibition of DNA gyrase leads to the disruption of DNA supercoiling, a necessary process for proper DNA function.

Key Findings:

• Bactericidal Concentration : Nalidixic acid exhibits optimal bactericidal activity against various gram-negative species at concentrations ranging from 50 to 200 µg/ml. At concentrations above this range, it tends to become bacteriostatic rather than bactericidal .
• Inhibition of Synthesis : Studies have shown that nalidixic acid inhibits deoxyribonucleic acid (DNA) synthesis without affecting ribonucleic acid (RNA) or protein synthesis at lower concentrations. However, at higher concentrations, it can inhibit both RNA and protein synthesis as well .

In Vitro Studies

Research has demonstrated nalidixic acid's effectiveness against several bacterial strains:

These findings highlight nalidixic acid's potency against enteric pathogens and its role in treating infections caused by these organisms .

Case Studies

• Urinary Tract Infections : A study involving patients with recurrent urinary tract infections revealed that nalidixic acid was effective in reducing bacterial load and improving clinical outcomes. The study reported a significant decrease in Escherichia coli counts post-treatment .
• Resistance Patterns : Recent data indicate a concerning trend in resistance among gram-negative bacteria to nalidixic acid. For instance, a retrospective analysis showed that 38.5% of isolated strains from blood cultures demonstrated resistance to nalidixic acid, suggesting an increasing prevalence of multi-drug-resistant organisms .

Comparative Studies with New Quinolones

Nalidixic acid has been compared with newer quinolone derivatives like ciprofloxacin and norfloxacin:

Newer quinolones exhibit superior antibacterial activity due to their improved pharmacokinetic properties and broader spectrum of action against resistant strains .