Ionophore A23187 shows anti-tuberculosis activity and synergy with tebipenem

Huang, Wei; Briffotaux, Julien; Wang, Xinwei; Liu, Huan; Hao, Pei; Cimino, Mena; Buchieri, Maria V.; Namouchi, Amine; Ainsa, Jose-Antonio; Gicquel, Brigitte

doi:10.1016/j.tube.2017.09.001

Cited by 7 publications

(7 citation statements)

References 31 publications

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“…Through continuous efforts to search for antibiotics that can effectively treat MDR pathogens, we found a polyether ionophore nigericin (NIG) has potent bactericidal ability against a variety of clinical MDR Gram-positive bacteria, including MRSA and VRE. NIG has been shown to have a broad spectrum of biological activities since 1960 ( Kevin Ii et al., 2009 ), including antibacterial activities against S. aureus , Bacillus cereus , Enterococcus faecalis and mycobacterial species ( Harold and Baarda, 1969 ; Wu et al., 2009 ; Huang et al., 2017 ). However, the antibacterial activity of NIG has not been systemically investigated.…”

Section: Introductionmentioning

confidence: 99%

Nigericin is effective against multidrug resistant gram-positive bacteria, persisters, and biofilms

Zhu

Hong

Sun

et al. 2022

Front. Cell. Infect. Microbiol.

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Multidrug-resistant (MDR) bacteria pose a significant clinical threat to human health, but the development of antibiotics cannot meet the urgent need for effective agents, especially those that can kill persisters and biofilms. Here, we reported that nigericin showed potent bactericidal activity against various clinical MDR Gram-positive bacteria, persisters and biofilms, with low frequencies of resistance development. Moreover, nigericin exhibited favorable in vivo efficacy in deep-seated mouse biofilm, murine skin and bloodstream infection models. With Staphylococcus aureus, nigericin disrupted ATP production and electron transport chain; cell death was associated with altered membrane structure and permeability. Obtaining nigericin-resistant/tolerant mutants required multiple rounds of challenge, and, cross-resistance to members of several antimicrobial classes was absent, probably due to distinct nigericin action with the GraSR two-component regulatory system. Thus, our work reveals that nigericin is a promising antibiotic candidate for the treatment of chronic or recurrent infections caused by Gram-positive bacteria.

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Section: Introductionmentioning

confidence: 99%

Nigericin is effective against multidrug resistant gram-positive bacteria, persisters, and biofilms

Zhu

Hong

Sun

et al. 2022

Front. Cell. Infect. Microbiol.

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“…In conclusion, we report the identification of a pump-based resistance mechanism to the spiroketal indolyl Mannich base lead SIMBL MmpL5-mediated resistance has been reported for multiple antimycobacterials (10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Downloaded Frommentioning

confidence: 74%

Resistance against Membrane-Inserting MmpL3 Inhibitor through Upregulation of MmpL5 in Mycobacterium tuberculosis

Nyantakyi

et al. 2020

Antimicrob Agents Chemother

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Spiroketal indolyl Mannich bases (SIMBs) present a novel class of membrane-inserting antimycobacterials with efficacy in a tuberculosis mouse model. SIMBs exert their antibacterial activity by two mechanisms. The indolyl Mannich base scaffold causes permeabilization of bacteria and the spiroketal moiety contributes to inhibition of the mycolic acid transporter MmpL3. Here, we show that low-level resistance to SIMBs arises by mutations in the transcriptional repressor MmpR5 resulting in upregulation of the efflux pump MmpL5.

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“…Studies by others showed the synergistic effect of CMN with tebipenem for antimycobacterial activity. 92 In our study, CMN was fungistatic with Cne. Other ionophores, such as salinomycin, monensin, and portmicin, were fungistatic toward Piromonas spp.…”

Section: ■ Resultsmentioning

confidence: 93%

“…Although CMN did not show synergistic antifungal activity with polymyxin B, we found that CMN had a synergistic antifungal effect with AmB and an additive effect with 5-FC. Studies by others showed the synergistic effect of CMN with tebipenem for antimycobacterial activity . In our study, CMN was fungistatic with Cne .…”

Section: Resultsmentioning

confidence: 99%

Calcimycin Inhibits Cryptococcus neoformans In Vitro and In Vivo by Targeting the Prp8 Intein Splicing

Tharappel

Zhu

et al. 2022

ACS Infect. Dis.

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Drug resistance is a significant concern in the treatment of diseases, including cryptococcosis caused by Cryptococcus neoformans (Cne) and Cryptococcus gattii (Cga). Alternative drug targets are necessary to overcome drug resistance before it attains a critical stage. Splicing of inteins from pro-protein precursors is crucial for activities of essential proteins hosting intein elements in many organisms, including human pathogens such as Cne and Cga. Through a high-throughput screening, we identified calcimycin (CMN) as a potent Prp8 intein splicing inhibitor with a minimum inhibitory concentration (MIC) of 1.5 μg/mL against the wild-type Cne-H99 (Cne-WT or Cne). In contrast, CMN inhibited the intein-less mutant strain (Cne-Mut) with a 16-fold higher MIC. Interestingly, Aspergillus fumigatus and a few Candida species were resistant to CMN. Further studies indicated that CMN reduced virulence factors such as urease activity, melanin production, and biofilm formation in Cne. CMN also inhibited Cne intracellular infection in macrophages. In a target-specific split nanoluciferase assay, the IC50 of CMN was 4.6 μg/mL. Binding of CMN to recombinant Prp8 intein was demonstrated by thermal shift assay and microscale thermophoresis. Treating Cne cells with CMN reduced intein splicing. CMN was fungistatic and showed a synergistic effect with the known antifungal drug amphotericin B. Finally, CMN treatment at 20 mg/kg body weight led to 60% reduction in lung fungal load in a cryptococcal pulmonary infection mouse model. Overall, CMN represents a potent antifungal with a novel mechanism of action to treat Cne and possibly Cga infections.

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Ionophore A23187 shows anti-tuberculosis activity and synergy with tebipenem

Cited by 7 publications

References 31 publications

Nigericin is effective against multidrug resistant gram-positive bacteria, persisters, and biofilms

Nigericin is effective against multidrug resistant gram-positive bacteria, persisters, and biofilms

Resistance against Membrane-Inserting MmpL3 Inhibitor through Upregulation of MmpL5 in Mycobacterium tuberculosis

Calcimycin Inhibits Cryptococcus neoformans In Vitro and In Vivo by Targeting the Prp8 Intein Splicing

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