scholarly journals In vitro activity of bedaquiline and imipenem against actively growing, nutrient-starved, and intracellular Mycobacterium abscessus

2021 ◽  
Author(s):  
Olumide Martins ◽  
Jin Lee ◽  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Kelly E. Dooley ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Tween 80 ◽  
Standard Of Care ◽  
Drug Regimen ◽  
Multidrug Resistant ◽  
Culture Conditions ◽  
Mycobacterium Abscessus ◽  
Infection Model ◽  
Treatment Regimens

Mycobacterium abscessus lung disease is difficult to treat due to intrinsic drug resistance and the persistence of drug-tolerant bacteria. Currently, the standard of care is a multi-drug regimen with at least 3 active drugs, preferably including a β-lactam (imipenem or cefoxitin). These regimens are lengthy, toxic, and have limited efficacy. The search for more efficacious regimens led us to evaluate bedaquiline, a diarylquinoline licensed for treatment of multidrug-resistant tuberculosis. We performed in vitro time-kill experiments to evaluate the activity of bedaquiline alone and in combination with the first-line drug imipenem against M. abscessus under various conditions. Against actively growing bacteria, bedaquiline was largely bacteriostatic and antagonized the bactericidal activity of imipenem. Contrarily, against nutrient-starved persisters, bedaquiline was bactericidal, while imipenem was not, and bedaquiline drove the activity of the combination. In an intracellular infection model, bedaquiline and imipenem had additive bactericidal effects. Correlations between ATP levels and the bactericidal activity of imipenem and its antagonism by bedaquiline were observed. Interestingly, the presence of Tween 80 in the media affected the activity of both drugs, enhancing the activity of imipenem and reducing that of bedaquiline. Overall, these results show that bedaquiline and imipenem interact differently depending on culture conditions. Previously reported antagonistic effects of bedaquiline on imipenem were limited to conditions with actively multiplying bacteria and/or the presence of Tween 80, whereas the combination was additive or indifferent against nutrient-starved and intracellular M. abscessus , where promising bactericidal activity of the combination suggests it may have a role in future treatment regimens.

scholarly journals In vitro activity of bedaquiline and imipenem against actively growing, nutrient-starved, and intracellular Mycobacterium abscessus

2021 ◽  
Author(s):  
Olumide Martins ◽  
Nicole Ammerman ◽  
Jin Lee ◽  
Amit Kaushik ◽  
Kelly E Dooley ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Tween 80 ◽  
Standard Of Care ◽  
Drug Regimen ◽  
Multidrug Resistant ◽  
Culture Conditions ◽  
Mycobacterium Abscessus ◽  
Infection Model ◽  
Treatment Regimens

Mycobacterium abscessus lung disease is difficult to treat due to intrinsic drug resistance and the persistence of drug-tolerant bacteria. Currently, the standard of care is a multi-drug regimen with at least 3 active drugs, preferably including a β-lactam (imipenem or cefoxitin). These regimens are lengthy, toxic, and have limited efficacy. The search for more efficacious regimens led us to evaluate bedaquiline, a diarylquinoline licensed for treatment of multidrug-resistant tuberculosis. We performed in vitro time-kill experiments to evaluate the activity of bedaquiline alone and in combination with the first-line drug imipenem against M. abscessus under various conditions. Against actively growing bacteria, bedaquiline was largely bacteriostatic and antagonized the bactericidal activity of imipenem. Contrarily, against nutrient-starved persisters, bedaquiline was bactericidal, while imipenem was not, and bedaquiline drove the activity of the combination. In an intracellular infection model, bedaquiline and imipenem had additive bactericidal effects. Correlations between ATP levels and the bactericidal activity of imipenem and its antagonism by bedaquiline were observed. Interestingly, the presence of Tween 80 in the media affected the activity of both drugs, enhancing the activity of imipenem and reducing that of bedaquiline. Overall, these results show that bedaquiline and imipenem interact differently depending on culture conditions. Previously reported antagonistic effects of bedaquiline on imipenem were limited to conditions with actively multiplying bacteria and/or the presence of Tween 80, whereas the combination was additive or indifferent against nutrient-starved and intracellular M. abscessus, where promising bactericidal activity of the combination suggests it may have a role in future treatment regimens.

scholarly journals Artemisia annua and Artemisia afra extracts exhibit strong bactericidal activity against Mycobacterium tuberculosis

2020 ◽  
Author(s):  
Maria Carla Martini ◽  
Tianbi Zhang ◽  
John T. Williams ◽  
Robert B. Abramovitch ◽  
Pamela J. Weathers ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bactericidal Activity ◽  
Artemisia Annua ◽  
Multidrug Resistant ◽  
Mycobacterium Abscessus ◽  
Major Barrier ◽  
Treatment Regimens ◽  
Tb Treatment ◽  
Emergence Of Resistance

ABSTRACTEthnopharmacological relevanceEmergence of drug-resistant and multidrug-resistant Mycobacterium tuberculosis (Mtb) strains is a major barrier to tuberculosis (TB) eradication, as it leads to longer treatment regimens and in many cases treatment failure. Thus, there is an urgent need to explore new TB drugs and combinations, in order to shorten TB treatment and improve outcomes. Here, we evaluate the potential of two medicinal plants, Artemisia annua, a natural source of artemisinin (AN), and Artemisia afra, as sources of novel antitubercular agents.Aim of the studyOur goal was to measure the activity of A. annua and A. afra extracts against Mtb as potential natural and inexpensive therapies for TB treatment, or as sources of compounds that could be further developed into effective treatments.Materials and MethodsThe minimum inhibitory concentrations (MICs) of A. annua and A. afra dichloromethane extracts were determined, and concentrations above the MICs were used to evaluate their ability to kill Mtb and Mycobacterium abscessus in vitro.ResultsPrevious studies showed that A. annua and A. afra inhibit Mtb growth. Here, we show for the first time that Artemisia extracts have a strong bactericidal activity against Mtb. The killing effect of A. annua was much stronger than equivalent concentrations of pure AN, suggesting that A. annua extracts kill Mtb through a combination of AN and additional compounds. A. afra, which produces very little AN, displayed bactericidal activity against Mtb that was substantial but weaker than that of A. annua. In addition, we measured the activity of Artemisia extracts against Mycobacterium abscessus. Interestingly, we observed that while A. annua is not bactericidal, it inhibits growth of M. abscessus, highlighting the potential of this plant in combinatory therapies to treat M. abscessus infections.ConclusionOur results indicate that Artemisia extracts have an enormous potential for treatment of TB and M. abscessus infections, and that these plants contain bactericidal compounds in addition to AN. Combination of extracts with existing antibiotics may not only improve treatment outcomes but also reduce the emergence of resistance to other drugs.

scholarly journals Etamycin as a Novel Mycobacterium abscessus Inhibitor

2020 ◽  
Vol 21 (18) ◽  
pp. 6908
Author(s):  
Bui Thi Bich Hanh ◽  
Tae Ho Kim ◽  
June-Woo Park ◽  
Da-Gyum Lee ◽  
Jae-Sung Kim ◽  
...  
Keyword(s):  
Wild Type Strain ◽  
Standard Of Care ◽  
Mycobacterium Abscessus ◽  
Drug Candidate ◽  
Infection Model ◽  
Excellent Activity ◽  
Further Development ◽  
Clinical Drug

The increase in drug-resistant Mycobacterium abscessus, which has become resistant to existing standard-of-care agents, is a major concern, and new antibacterial agents are strongly needed. In this study, we introduced etamycin that showed an excellent activity against M. abscessus. We found that etamycin significantly inhibited the growth of M. abscessus wild-type strain, three subspecies, and clinical isolates in vitro and inhibited the growth of M. abscessus that resides in macrophages without cytotoxicity. Furthermore, the in vivo efficacy of etamycin in the zebrafish (Danio rerio) infection model was greater than that of clarithromycin, which is recommended as the core agent for treating M. abscessus infections. Thus, we concluded that etamycin is a potential anti-M. abscessus candidate for further development as a clinical drug candidate.

scholarly journals Differential in vitro activity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starved Mycobacterium abscessus

2020 ◽  
Author(s):  
Jin Lee ◽  
Nicole Ammerman ◽  
Anusha Agarwal ◽  
Maram Naji ◽  
Si-Yang Li ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Current Treatment ◽  
Mycobacterium Abscessus ◽  
Bacterial Populations ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Limited Effectiveness ◽  
Dependent Activity

AbstractCurrent treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net non-replicating M. abscessus populations in nutrient-rich and nutrient starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing M. abscessus, respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and non-replicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved M. abscessus. Overall, these in vitro data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for M. abscessus infections. This rich dataset of differential time-and concentration-dependent activity of drugs, alone and together, against M. abscessus also highlights several issues affecting interpretation and translation of in vitro findings.

scholarly journals In Vitro and In Vivo Activities of PD 0305970 and PD 0326448, New Bacterial Gyrase/Topoisomerase Inhibitors with Potent Antibacterial Activities versus Multidrug-Resistant Gram-Positive and Fastidious Organism Groups

2007 ◽  
Vol 51 (4) ◽  
pp. 1191-1201 ◽  
Author(s):  
Michael D. Huband ◽  
Michael A. Cohen ◽  
Margaret Zurack ◽  
Debra L. Hanna ◽  
Laura A. Skerlos ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Legionella Pneumophila ◽  
Bacterial Species ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Topoisomerase Inhibitors ◽  
Gram Positive ◽  
Resistant Mutants

ABSTRACT PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors (quinazoline-2,4-diones) that possess outstanding in vitro and in vivo activities against a wide spectrum of bacterial species including quinolone- and multidrug-resistant gram-positive and fastidious organism groups. The respective MICs (μg/ml) for PD 0305970 capable of inhibiting ≥90% of bacterial strains tested ranged from 0.125 to 0.5 versus staphylococci, 0.03 to 0.06 versus streptococci, 0.25 to 2 versus enterococci, and 0.25 to 0.5 versus Moraxella catarrhalis, Haemophilus influenzae, Listeria monocytogenes, Legionella pneumophila, and Neisseria spp. PD 0326448 MIC90s were generally twofold higher versus these same organism groups. Comparative quinolone MIC90 values were 4- to 512-fold higher than those of PD 0305970. In testing for frequency of resistance, PD 0305970 and levofloxacin showed low levels of development of spontaneous resistant mutants versus both Staphylococcus aureus and Streptococcus pneumoniae. Unlike quinolones, which target primarily gyrA and parC, analysis of resistant mutants in S. pneumoniae indicates that the likely targets of PD 0305970 are gyrB and parE. PD 0305970 demonstrated rapid bactericidal activity by in vitro time-kill testing versus streptococci. This bactericidal activity carried over to in vivo testing, where PD 0305970 and PD 0326448 displayed outstanding Streptococcus pyogenes 50% protective doses (PD50s) (oral dosing) of 0.7 and 3.6 mg/kg, respectively (ciprofloxacin and levofloxacin PD50s were >100 and 17.7 mg/kg, respectively). PD 0305970 was also potent in a pneumococcal pneumonia mouse infection model (PD50 = 3.2 mg/kg) and was 22-fold more potent than levofloxacin.

scholarly journals Differential in vitro activity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starved Mycobacterium abscessus

2020 ◽  
Author(s):  
Jin Lee ◽  
Nicole Ammerman ◽  
Anusha Agarwal ◽  
Maram Naji ◽  
Si-Yang Li ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Current Treatment ◽  
Mycobacterium Abscessus ◽  
Bacterial Populations ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Limited Effectiveness ◽  
Dependent Activity

Current treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net non-replicating M. abscessus populations in nutrient-rich and nutrient starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing M. abscessus, respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and non-replicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved M. abscessus. Overall, these in vitro data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for M. abscessus infections. This rich dataset of differential time- and concentration-dependent activity of drugs, alone and together, against M. abscessus also highlights several issues affecting interpretation and translation of in vitro findings.

scholarly journals Activities of Moxifloxacin in Combination with Macrolides against Clinical Isolates of Mycobacterium abscessus and Mycobacterium massiliense

2012 ◽  
Vol 56 (7) ◽  
pp. 3549-3555 ◽  
Author(s):  
Go-Eun Choi ◽  
Ki-Nam Min ◽  
Choul-Jae Won ◽  
Kyeongman Jeon ◽  
Sung Jae Shin ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Ex Vivo ◽  
Synergistic Effects ◽  
Mycobacterium Abscessus ◽  
Infection Model ◽  
Content Type ◽  
Treatment Regimens ◽  
Mycobacterium Massiliense

ABSTRACTInfections caused byMycobacterium abscessusandMycobacterium massilienseare on the rise among humans. Although macrolides, including clarithromycin (CLR) and azithromycin (AZM), are key antibiotics for the treatment ofM. abscessusandM. massilienseinfections, treatment regimens for these infections are still largely undefined. In this study, we evaluated thein vitro,ex vivo, andin vivoactivities of moxifloxacin (MXF) in combination with macrolides against clinically isolatedM. abscessusandM. massiliensestrains. Overall, CLR, AZM, and MXF alone showed activity against both speciesin vitro,ex vivo, andin vivo. When MXF was combined with a macrolide againstM. abscessusisolates, antagonism was observed in 65.4% (17/26) of the strains with CLR and 46.2% (12/26) of the strains with AZMin vitroas well as in 66.7% (10/15) of the strains with CLR and 40.0% (6/15) of the strains with AZM in macrophages as determined by the fractional inhibitory concentration index. In contrast, either indifferent or synergistic effects of the MXF-macrolide combinations were observed against onlyM. massiliensestrains. Moreover, a murine infection model showed similar results. Antagonism between the MXF and macrolide combinations was observed in five out of sevenM. abscessusstrains, while indifferent and synergistic effects for these combinations were observed for three of the sixM. massiliensestrains tested, respectively. In conclusion, the activity of MXF in combination with a macrolide differed forM. abscessusandM. massilienseinfections and the addition of MXF to macrolide therapy had no benefit for the treatment ofM. abscessusinfections.

scholarly journals Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169)

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Andréanne Lupien ◽  
Anthony Vocat ◽  
Caroline Shi-Yan Foo ◽  
Emilyne Blattes ◽  
Jean-Yves Gillon ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Exposure ◽  
Antitubercular Activity ◽  
Drug Regimen ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Content Type ◽  
Treatment Regimens

ABSTRACT The efficacy of the standardized four-drug regimen (comprising isoniazid, rifampin, pyrazinamide, and ethambutol) for the treatment of tuberculosis (TB) is menaced by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. Intensive efforts have been made to develop new antibiotics or to repurpose old drugs, and several of these are currently being evaluated in clinical trials for their antitubercular activity. Among the new candidate drugs is macozinone (MCZ), the piperazine-containing benzothiazinone PBTZ169, which is currently being evaluated in phase I/II clinical trials. Here, we determined the in vitro and in vivo activity of MCZ in combination with a range of anti-TB drugs in order to design a new regimen against active TB. Two-drug combinations with MCZ were tested against M. tuberculosis using checkerboard and CFU enumeration after drug exposure assays. MCZ was observed to have no interactions with all first- and second-line anti-TB drugs. At the MIC of each drug, MCZ with either bedaquiline (BDQ), clofazimine (CLO), delamanid (DMD), or sutezolid (STZ) reduced the bacterial burden by 2 logs compared to that achieved with the drugs alone, indicating synergism. MCZ also displayed synergism with clomiphene (CLM), a potential inhibitor of the undecaprenyl pyrophosphate synthase (UppS) in mycobacteria. For all the other drugs tested in combination with MCZ, no synergistic activity was observed. Neither antagonism nor increased cytotoxicity was found for most combinations, suggesting that MCZ could be added to different TB treatment regimens without any significant adverse effects.

scholarly journals Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements

2021 ◽  
Author(s):  
Jonah Larkins-Ford ◽  
Yonatan N. Degefu ◽  
Nhi Van ◽  
Artem Sokolov ◽  
Bree B. Aldridge
Keyword(s):  
Standard Of Care ◽  
Search Space ◽  
Multidrug Resistant ◽  
Drug Combinations ◽  
Effective Drug ◽  
Preclinical Model ◽  
Combination Drug ◽  
Growth Environment ◽  
Treatment Regimens

AbstractA challenge in designing treatment regimens for tuberculosis is the necessity to use three or more antibiotics in combination. The combination space is too large to be comprehensively assayed; therefore, only a small number of possible combinations are tested. We narrowed the prohibitively large search space of combination drug responses by breaking down high-order combinations into units of drug pairs. Using pairwise drug potency and drug interaction metrics from in vitro experiments across multiple growth environments, we trained machine learning models to predict outcomes associated with higher-order combinations in the BALB/c relapsing mouse model, an important preclinical model for drug development. We systematically predicted treatment outcomes of >500 combinations among twelve antibiotics. Our classifiers performed well on test data and predicted many novel combinations to be improved over bedaquiline + pretomanid + linezolid, an effective regimen for multidrug-resistant tuberculosis that also shortens treatment in BALB/c mice compared to the standard of care. To understand the design features of effective drug combinations, we reformulated classifiers as simple rulesets to reveal guiding principles of constructing combination therapies for both preclinical and clinical outcomes. One example ruleset is to include a drug pair that is synergistic in dormancy and another pair that is potent in a cholesterol-rich growth environment. These rulesets are predictive, intuitive, and practical, thus enabling rational construction of effective drug combinations based on in vitro pairwise drug synergies and potencies. As more preclinical and clinical drug combination data become available, we expect to improve predictions and combination design rules.

Apramycin overcomes the inherent lack of antimicrobial bactericidal activity in Mycobacterium abscessus

2021 ◽  
Author(s):  
Petra Selchow ◽  
Diane J. Ordway ◽  
Deepshikha Verma ◽  
Nicholas Whittel ◽  
Aline Petrig ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Lung Infection ◽  
Resistance Mechanisms ◽  
Mycobacterium Abscessus ◽  
Multi Drug Resistance ◽  
Emerging Pathogen ◽  
Aminoglycoside Resistance ◽  
Treatment Regimens ◽  
Distinct Structure ◽  
Poor Therapeutic Outcome

Antibiotic therapy of infections caused by the emerging pathogen Mycobacterium abscessus is challenging due to the organism’s inherent resistance towards clinically available antimicrobials. The low bactericidal potency of currently available treatment regimens is of concern and testifies to the poor therapeutic outcome in pulmonary M. abscessus infections. Mechanistically, we here demonstrate that the acetyltransferase Eis2 is responsible for the lack of bactericidal activity of amikacin, the standard aminoglycoside used in combination treatment. In contrast, the distinct structure aminoglycoside apramycin is not modified by any of the pathogen’s innate aminoglycoside resistance mechanisms nor is it affected by the multi-drug resistance regulator WhiB7. As a consequence, apramycin uniquely shows potent bactericidal activity against M. abscessus . This favourable feature of apramycin is reflected in a mouse model of M. abscessus lung infection, which demonstrates superior activity over amikacin. These findings encourage the development of apramycin for the treatment of M. abscessus infections and suggest that M. abscessus eradication in lung pulmonary disease may be within therapeutic reach.

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