Aminoglycoside Therapy for Tuberculosis: Evidence for Ototoxicity among Tuberculosis Patients in Ghana

Owusu, Enid; Amartey, B.T.; Afutu, Emmanuel; Boafo, Neal

doi:10.3390/diseases10010010

Cited by 9 publications

(1 citation statement)

References 34 publications

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“…Spectinomycin, an aminocyclitol antibiotic, is a broad spectrum antibiotic used mainly for the treatment of Neisseria gonorrhoeae (11). It inhibits bacterial protein synthesis (12) and has an acceptable safety profile with no known ototoxicity and nephrotoxicity (13,14). The activity of spectinomycin against Mtb is very poor but its structural modification led to the development of a new series of semisynthetic analogs called spectinamides (12,15,16).…”

Section: Introductionmentioning

confidence: 99%

A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides

Ali,

Dutt,

MacNeill

et al. 2023

Preprint

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The Nix-TB clinical trial evaluated a new 6-month regimen containing three-oral-drugs; bedaquiline (B), pretomanid (Pa) and linezolid (L) (BPaL regimen) for treatment of tuberculosis (TB). This regimen achieved remarkable results as almost 90% of the multidrug resistant (MDR) or extensively drug resistant (XDR) TB participants were cured but many patients also developed severe adverse effects (AEs). The AEs were associated with the long-term administration of the protein synthesis inhibitor linezolid. Spectinamide 1599 (S) is also a protein synthesis inhibitor ofMycobacterium tuberculosiswith an excellent safety profile but which lacks oral bioavailability. Here we hypothesize that inhaled spectinamide 1599, combined with BPa ––BPaS regimen––has similar efficacy to that of BPaL regimen while simultaneously avoiding the L-associated AEs. The BPaL and BPaS regimens were compared in the Balb/c and C3HeB/FeJ murine chronic TB efficacy models. After 4-weeks of treatment, both regimens promoted equivalent bactericidal effect in both TB murine models. However, treatment with BPaL resulted in significant weight loss and the complete blood count suggested development of anemia. These effects were not similarly observed in mice treated with BPaS. BPaL treatment also decreased myeloid to erythroid ratio and increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. During therapy both regimens improved the lung lesion burden, reduced neutrophil and cytotoxic T cells counts while increased the number of B and helper and regulatory T cells. These combined data suggest that inhaled spectinamide 1599 combined with BPa is an effective TB regimen that avoids L-associated AEs.IMPORTANCETuberculosis (TB) is an airborne infectious disease that spreads via aerosols containingMycobacterium tuberculosis(Mtb), the causative agent of TB. TB can be cured by administration of 3-4 drugs for 6-9 months but there are limited treatment options for patients infected with multidrug (MDR) and extensively resistant (XDR) strains of Mtb. BPaL is a new all-oral combination of drugs consisting of Bedaquiline (B), Pretomanid (Pa) and Linezolid (L). This regimen was able to cure ∼90% of MDR and XDR TB patients in clinical trials but many patients developed severe adverse effects (AEs) associated to the long-term administration of linezolid. We evaluated a new regimen in which Linezolid in the BPaL regimen was replaced with inhaled spectinamide 1599. In the current study, we demonstrate that 4-weeks of treatment with inhaled spectinamide 1599 in combination with Bedaquiline and Pretomanid has equivalent efficacy to the BPaL drug combination and avoids the L-associated-AEs.

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Section: Introductionmentioning

confidence: 99%

A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides

Ali,

Dutt,

MacNeill

et al. 2023

Preprint

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Isoniazid Hybrids As Potential Antitubercular Agents

Mishra,

Kumar,

Singh

2024

ChemistrySelect

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The rapid emergence of various forms of drug‐resistant tuberculosis (TB) has massively impacted people's health globally. According to the WHO, TB care and facilities have been downgraded by 21% since the COVID‐19 pandemic, which has further slowed down the progress toward the “End TB Strategy.” Multiple studies have shown drug‐resistant tuberculosis to be resilient to front‐line antituberculosis drugs, including isoniazid (INH), thus constantly prompting researchers worldwide to probe new potent chemical entities to replace/supplement the current artillery of anti‐TB therapeutics. The molecular hybridization (MH) technique has recently been adopted by many synthetic and medicinal chemists to combine different pharmacophoric units into a single molecular architecture which in most cases has been reported to exhibit a better pharmacological profile as compared to its precursors. The present review provides a concise account of the MH hybridization strategies directed at the structural manipulations of isoniazid to develop new anti‐TB agents and their structure‐activity relationships. Furthermore, their toxicity profiles and docking studies with relevant receptors are also briefly discussed.

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