Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening

Arenaz-Callao, María Pilar; Río, Rubén González del; Quintana, Ainhoa Lucía; Thompson, Charles J.; Mendoza-Losana, Alfonso; Ramón-García, Santiago

doi:10.1371/journal.pntd.0007126

Cited by 15 publications

(26 citation statements)

References 62 publications

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“…Here, we evaluated the emergence of resistance to a combination of a β-lactam (CEF) and rifampicin (RIF). These two drugs are synergistic in B. subtilis , as shown also for other bacteria ( 56 – 59 ). We used in vitro evolution followed by whole-genome sequencing to identify mutations that enable growth in the presence of this dual selection.…”

Section: Discussionsupporting

confidence: 58%

Mutations in rpoB That Confer Rifampicin Resistance Can Alter Levels of Peptidoglycan Precursors and Affect β-Lactam Susceptibility

Patel

Soni

Rhee

et al. 2023

mBio

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Section: Discussionsupporting

confidence: 58%

Mutations in rpoB That Confer Rifampicin Resistance Can Alter Levels of Peptidoglycan Precursors and Affect β-Lactam Susceptibility

Patel

Soni

Rhee

et al. 2023

mBio

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“…Here, we evaluated the emergence of resistance to a combination of a β-lactam (CEF) and rifampicin (RIF). These two drugs are synergistic in B. subtilis, as shown also for other bacteria (53)(54)(55)(56). We used in vitro evolution followed by whole-genome sequencing to identify mutations that enable growth in the presence of this dual selection.…”

Section: Discussionmentioning

confidence: 94%

Mutations inrpoBthat confer rifampicin resistance can alter levels of peptidoglycan precursors and affect β-lactam susceptibility

Patel

Soni

Rhee

et al. 2022

Preprint

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Bacteria can adapt to stressful conditions through mutations affecting the RNA polymerase core subunits that lead to beneficial changes in transcription. In response to selection with rifampicin (RIF), mutations arise in the RIF resistance determining region (RRDR) ofrpoBthat reduce antibiotic binding. These changes can also alter transcription and thereby have pleiotropic effects on bacterial fitness. Here, we studied the evolution of resistance in Bacillus subtilis to the synergistic combination of RIF and the β-lactam cefuroxime (CEF). Two independent evolution experiments led to the recovery of a single rpoB allele (S487L) that was able to confer resistance to RIF and CEF through a single mutation. Two other common RRDR mutations made the cells 32x more sensitive to CEF (H482Y) or led to only modest CEF resistance (Q469R). The diverse effects of these three mutations on CEF resistance are correlated with differences in the expression of peptidoglycan (PG) synthesis genes and in the levels of two metabolites crucial in regulating PG synthesis, glucosamine-6-phosphate (GlcN-6-P) and UDP-N-acetylglucosamine (UDP-GlcNAc). We conclude that RRDR mutations can have widely varying effects on pathways important for cell wall biosynthesis, and this may restrict the spectrum of mutations that arise during combination therapy.

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“…Interestingly, zidovudine displayed strong synergy with both drugs. We thus aimed to characterize whether the addition of zidovudine to the fosfomycin/colistin combination could further potentiate the synergistic interaction, as previously described (24,30,31). The triple combination was highly active showing bactericidal activity to the limit of detection in 4 out of 8 strains tested.…”

Section: Resultsmentioning

confidence: 99%

“…Given that our studies demonstrated that zidovudine-based combinations are more potent than currently clinically used for the treatment of infections caused by MDR/XDR K. pneumoniae strains, we performed TKA to characterize the potential impact of zidovudine in a triple combination with fosfomycin and colistin. In mycobacteria, triple combinations perform better than the sum of the pairwise combinations (24,30,31); however, this was not the case and the triple combination added little value to fosfomycin/colistin ( Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

Zidovudine multi-combos with last-line fosfomycin, ceftazidime-avibactam, colistin and tigecycline against Multi-Drug Resistant Klebsiella pneumoniae

Gómara-Lomero

López-Calleja

Rezusta

et al. 2022

Preprint

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Drug repurposing is a novel strategy for the development of new therapies against antibiotic-resistant bacteria. Zidovudine, an antiviral largely used in the HIV-therapy, exerts antibacterial activity against Gram-negative bacteria. Zidovudine was identified in a previous drug repurposing synergy screening as fosfomycin enhancer against Klebsiella pneumoniae ATCC 13883. Our aim was to evaluate the antibacterial in vitro activity of zidovudine-based combinations with last-line antibiotics against MDR/XDR K. pneumoniae isolates. We validated the zidovudine/fosfomycin combination against a collection of 12 MDR K. pneumoniae isolates by the checkerboard assay (CBA). In addition, we performed time-kill assays (TKA) to analyze synergistic and bactericidal activities of zidovudine paired combinations with fosfomycin, ceftazidime-avibactam, colistin and tigecycline. These were compared with frequent clinical combinations in the treatment of MDR Enterobacteriaceae. The potential of the triple zidovudine/fosfomycin/colistin was also assessed by TKA. CBA synergy confirmation rate between zidovudine/fosfomycin was 83.33%. TKA yielded synergy confirmation rates of 83.3% for zidovudine/ceftazidime-avibactam, 75% for zidovudine/fosfomycin, 75% for zidovudine/colistin and 66.6% for zidovudine/tigecycline with potent killing activities. Frequent clinical combinations displayed synergy rates of 41.6% for meropenem/ertapenem, 33.33% for meropenem/colistin, 75% for fosfomycin/colistin and 66.6% for fosfomycin/tigecycline with lower bactericidal efficacy than zidovudine-based combinations. The triple zidovudine/fosfomycin/colistin combination exhibited activities similar to fosfomycin/colistin and fosfomycin/zidovudine. As conclusion, zidovudine is an effective partner in in vitro combinations with existing antibiotics against MDR K. pneumoniae, especially with ceftazidime-avibactam, fosfomycin or colistin. Further studies are needed to elucidate the clinical potential of zidovudine as a repurposed drug in the antibacterial therapy.

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Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening

Cited by 15 publications

References 62 publications

Mutations in rpoB That Confer Rifampicin Resistance Can Alter Levels of Peptidoglycan Precursors and Affect β-Lactam Susceptibility

Mutations in rpoB That Confer Rifampicin Resistance Can Alter Levels of Peptidoglycan Precursors and Affect β-Lactam Susceptibility

Mutations inrpoBthat confer rifampicin resistance can alter levels of peptidoglycan precursors and affect β-lactam susceptibility

Zidovudine multi-combos with last-line fosfomycin, ceftazidime-avibactam, colistin and tigecycline against Multi-Drug Resistant Klebsiella pneumoniae

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