-
BioMed Research International 2018Nontuberculous mycobacteria (NTM) cause various diseases in humans and animals. Recently, the prevalence of NTM-related disease has been on the rise, becoming an...
OBJECTIVE
Nontuberculous mycobacteria (NTM) cause various diseases in humans and animals. Recently, the prevalence of NTM-related disease has been on the rise, becoming an emerging public health problem. The aim of this study was to determine the antibiotic susceptibility profiles of clinical isolates of . We performed susceptibility tests on 37 clinical NTM isolates to 30 antibiotics with the microdilution method recommended by the Clinical and Laboratory Standards Institute.
RESULTS
Both and were highly resistant to antitubercular drugs such as isoniazid, rifampin, ethambutol, clofazimine, ethionamide, and rifabutin. showed the lowest resistant rates to cefoxitin (10%), azithromycin (10%), amikacin (10%), and clarithromycin (20%) and very high resistant to sulfamethoxazole, vancomycin, oxacillin, clindamycin, and all fluoroquinolones. showed low resistance to tigecycline (0%), tetracycline (0%), cefmetazole (12%), imipenem (12%), linezolid (18%), and the aminoglycosides amikacin (0%), tobramycin (0%), neomycin (0%), and gentamycin (24%).
CONCLUSION
Amikacin, cefoxitin, and azithromycin have the highest activity against . Isolates of need to be individually evaluated for drug susceptibility before choosing an effective antimicrobial regimen for treatment of infections.
Topics: Anti-Bacterial Agents; Humans; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Mycobacterium fortuitum
PubMed: 30687747
DOI: 10.1155/2018/4902941 -
Expert Opinion on Drug Discovery Sep 2019: The treatment of lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key... (Review)
Review
: The treatment of lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen. : In this review, the authors discuss the rifamycins as a reemerging drug class for treating infections. The authors focus on the differential potency of rifampicin and rifabutin against in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated. : While repurposing rifabutin for lung disease may provide some immediate relief, the repositioning (chemical optimization) of rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve 'bacterial cell pharmacokinetics', better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen.
Topics: Animals; Anti-Bacterial Agents; Drug Repositioning; Humans; Lung Diseases; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Rifabutin; Rifampin; Rifamycins
PubMed: 31195849
DOI: 10.1080/17460441.2019.1629414 -
Antimicrobial Agents and Chemotherapy Oct 2020is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there...
is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there is an unmet medical need for effective treatments. Repurposing of clinically validated pharmaceuticals represents an attractive option for the development of chemotherapeutic alternatives against infections. In this context, rifabutin (RFB) has been shown to be active against and has raised renewed interest in using rifamycins for the treatment of pulmonary diseases. Here, we compared the and activity of RFB against the smooth and rough variants of , differing in their susceptibility profiles to several drugs and physiopathologial characteristics. While the activity of RFB is greater against rough strains than in smooth strains , suggesting a role of the glycopeptidolipid layer in susceptibility to RFB, both variants were equally susceptible to RFB inside human macrophages. RFB treatment also led to a reduction in the number and size of intracellular and extracellular mycobacterial cords. Furthermore, RFB was highly effective in a zebrafish model of infection and protected the infected larvae from -induced killing. This was corroborated by a significant reduction in the overall bacterial burden, as well as decreased numbers of abscesses and cords, two major pathophysiological traits in infected zebrafish. This study indicates that RFB is active against both and , further supporting its potential usefulness as part of combination regimens targeting this difficult-to-treat mycobacterium.
Topics: Animals; Anti-Bacterial Agents; Humans; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Rifabutin; Zebrafish
PubMed: 32816730
DOI: 10.1128/AAC.00363-20 -
Antimicrobial Agents and Chemotherapy Jul 2020Therapeutic options for infections are extremely limited. New or repurposed drugs are needed. The anti- activity of AR-12 (OSU-03012), reported to express...
Therapeutic options for infections are extremely limited. New or repurposed drugs are needed. The anti- activity of AR-12 (OSU-03012), reported to express broad-spectrum antimicrobial effects, was investigated and Antimicrobial susceptibility testing was performed on 194 clinical isolates. Minimum bactericidal concentration and time-kill kinetics assays were conducted to distinguish the bactericidal versus bacteriostatic activity of AR-12. Synergy between AR-12 and five clinically important antibiotics was determined using a checkerboard synergy assay. The activity of AR-12 against intracellular residing within macrophage was also evaluated. Finally, the potency of AR-12 was determined in a neutropenic mouse model that mimics pulmonary infection. AR-12 exhibited high anti- activity , with an MIC of 4 mg/liter (8.7 μM) and an MIC of 8 mg/liter (17.4 μM) for both subsp. and subsp. AR-12 and amikacin exhibited comparable bactericidal activity against extracellular in culture. AR-12, however, exhibited significantly greater intracellular antibacterial activity than amikacin and caused a significant reduction in the bacterial load in the lungs of neutropenic mice infected with No antagonism between AR-12 and clarithromycin, amikacin, imipenem, cefoxitin, or tigecycline was evident. In conclusion, AR-12 is active against and and does not antagonize the most frequently used anti- drugs. As such, AR-12 is a potential candidate to include in novel strategies to treat infections.
Topics: Animals; Anti-Bacterial Agents; Clarithromycin; Mice; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Pyrazoles; Sulfonamides
PubMed: 32482678
DOI: 10.1128/AAC.00236-20 -
Nature Communications Jun 2023Mycobacterium abscessus (Mab) infections are inexplicably intractable to clearing after aggressive and lengthy treatment regimens. Here we discovered that acquisition of...
Mycobacterium abscessus (Mab) infections are inexplicably intractable to clearing after aggressive and lengthy treatment regimens. Here we discovered that acquisition of a single toxin-antitoxin system enables Mab to activate a phenotypic switch that enhances survival upon treatment with current first-line antibiotics. This switch is tripped when the VapC5 toxin inactivates tRNA by cleavage at only one site within its anticodon, leading to growth arrest. Concomitant tRNA depletion then reprograms the transcriptome to favor synthesis of proteins naturally low in the cognate Ser UCG codon including the transcription factor WhiB7 and members of its regulon as well as the ribosomal protein family. This programmed stockpiling of ribosomes is predicted to override the efficacy of ribosome-targeting antibiotics while the growth arrest phenotype attenuates antibiotics targeting cell wall synthesis. In agreement, VapC5 increases Mab persister formation upon exposure to amikacin and the next-generation oxazolidinone tedizolid (both target ribosomes) or cefoxitin (inhibits cell wall synthesis). These findings expand the repertoire of genetic adaptations harnessed by Mab to survive assaults intended to eradicate it, as well as provide a much-needed framework for selection of shorter and more efficacious alternate treatment options for Mab infections using currently available antimicrobials whose targets are not confounded by VapC5.
Topics: Anti-Bacterial Agents; Mycobacterium abscessus; Ribosomes; Anti-Infective Agents; Toxins, Biological; RNA, Transfer
PubMed: 37349306
DOI: 10.1038/s41467-023-38844-4 -
International Journal of Infectious... Jul 2017The differentiation between Mycobacterium abscessus subspecies abscessus (M. abscessus) and Mycobacterium abscessus subspecies massiliense (M. massiliense) and...
OBJECTIVES
The differentiation between Mycobacterium abscessus subspecies abscessus (M. abscessus) and Mycobacterium abscessus subspecies massiliense (M. massiliense) and determination of the presence of inducible resistance to macrolide antibiotics are important factors in the management of patients with Mycobacterium abscessus complex (MABC) infections. Unlike pulmonary MABC infections, little information on extrapulmonary MABC infections is available.
METHODS
The molecular identification of clinical isolates was performed, and the clinical characteristics and treatment outcomes of 20 consecutive patients with extrapulmonary MABC infections were assessed.
RESULTS
M. abscessus and M. massiliense each caused 10 (50%) of the cases. Eight (80%) M. abscessus isolates that had inducible resistance to clarithromycin harbored an intact erm(41) gene of the T28 variant, whereas two (20%) M. abscessus isolates had the C28 erm(41) variant and were susceptible to clarithromycin. All M. massiliense isolates had a truncated erm(41) gene and were susceptible to clarithromycin. The drug susceptibility profiles other than clarithromycin were similar for the M. abscessus and M. massiliense isolates. Of the 20 patients, 17 (85%) showed a favorable outcome, including all patients with M. massiliense infection and 70% (7/10) of patients with M. abscessus infection. Favorable outcomes were associated with M. massiliense and M. abscessus isolates with a non-functional erm(41) gene (p=0.049).
CONCLUSIONS
Precise species and subspecies identification and the determination of macrolide susceptibility are recommended for the optimal treatment of extrapulmonary MABC infections.
Topics: Adult; Aged; Anti-Bacterial Agents; Clarithromycin; Drug Resistance, Bacterial; Female; Humans; Male; Methyltransferases; Microbial Sensitivity Tests; Middle Aged; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Retrospective Studies; Treatment Outcome
PubMed: 28522316
DOI: 10.1016/j.ijid.2017.05.007 -
Proceedings of the National Academy of... May 2023() is a multidrug-resistant pathogen increasingly responsible for severe pulmonary infections. Analysis of whole-genome sequences (WGS) of demonstrates dense genetic...
() is a multidrug-resistant pathogen increasingly responsible for severe pulmonary infections. Analysis of whole-genome sequences (WGS) of demonstrates dense genetic clustering of clinical isolates collected from disparate geographic locations. This has been interpreted as supporting patient-to-patient transmission, but epidemiological studies have contradicted this interpretation. Here, we present evidence for a slowing of the molecular clock rate coincident with the emergence of phylogenetic clusters. We performed phylogenetic inference using publicly available WGS from 483 patient isolates. We implement a subsampling approach in combination with coalescent analysis to estimate the molecular clock rate along the long internal branches of the tree, indicating a faster long-term molecular clock rate compared to branches within phylogenetic clusters. We used ancestry simulation to predict the effects of clock rate variation on phylogenetic clustering and found that the degree of clustering in the observed phylogeny is more easily explained by a clock rate slowdown than by transmission. We also find that phylogenetic clusters are enriched in mutations affecting DNA repair machinery and report that clustered isolates have lower spontaneous mutation rates in vitro. We propose that adaptation to the host environment through variation in DNA repair genes affects the organism's mutation rate and that this manifests as phylogenetic clustering. These results challenge the model that phylogenetic clustering in is explained by person-to-person transmission and inform our understanding of transmission inference in emerging, facultative pathogens.
Topics: Humans; Mycobacterium abscessus; Mutation Rate; Phylogeny; Mutation
PubMed: 37216535
DOI: 10.1073/pnas.2302033120 -
Microbiology Spectrum Dec 2022The prevalence of lung disease caused by Mycobacterium abscessus is increasing among patients with cystic fibrosis. M. abscessus is a multidrug resistant opportunistic...
The prevalence of lung disease caused by Mycobacterium abscessus is increasing among patients with cystic fibrosis. M. abscessus is a multidrug resistant opportunistic pathogen that is notoriously difficult to treat due to a lack of efficacious therapeutic regimens. Currently, there are no standard regimens, and treatment guidelines are based empirically on drug susceptibility testing. Thus, novel antibiotics are required. Natural products represent a vast pool of biologically active compounds that have a history of being a good source of antibiotics. Here, we screened a library of 517 natural products purified from fermentations of various bacteria, fungi, and plants against M. abscessus ATCC 19977. Lysobactin and sorangicin A were active against the M. abscessus complex and drug resistant clinical isolates. These natural products merit further consideration to be included in the M. abscessus drug pipeline. The many thousands of people living with cystic fibrosis are at a greater risk of developing a chronic lung infection caused by Mycobacterium abscessus. Since M. abscessus is clinically resistant to most anti-TB drugs available, treatment options are limited to macrolides. Despite macrolide-based therapies, cure rates for M. abscessus lung infections are 50%. Using an in-house library of curated natural products, we identified lysobactin and sorangicin A as novel scaffolds for the future development of antimicrobials for patients with M. abscessus infections.
Topics: Humans; Mycobacterium abscessus; Cystic Fibrosis; Mycobacterium Infections, Nontuberculous; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Anti-Bacterial Agents; Macrolides
PubMed: 36342177
DOI: 10.1128/spectrum.02672-22 -
Molecules (Basel, Switzerland) Oct 2022Unlike Tuberculosis (TB), lung disease is a highly drug-resistant bacterial infection with no reliable treatment options. De novo drug discovery is urgently needed but... (Review)
Review
Unlike Tuberculosis (TB), lung disease is a highly drug-resistant bacterial infection with no reliable treatment options. De novo drug discovery is urgently needed but is hampered by the bacterium's extreme drug resistance profile, leaving the current drug pipeline underpopulated. One proposed strategy to accelerate de novo drug discovery is to prioritize screening of advanced TB-active compounds for anti- activity. This approach would take advantage of the greater chance of homologous drug targets between mycobacterial species, increasing hit rates. Furthermore, the screening of compound series with established structure-activity-relationship, pharmacokinetic, and tolerability properties should fast-track the development of in vitro anti- hits into lead compounds with in vivo efficacy. In this review, we evaluated the effectiveness of this strategy by examining the literature. We found several examples where the screening of advanced TB chemical matter resulted in the identification of anti- compounds with in vivo proof-of-concept, effectively populating the drug pipeline with promising new candidates. These reports validate the screening of advanced TB chemical matter as an effective means of fast-tracking drug discovery.
Topics: Humans; Mycobacterium abscessus; Mycobacterium; Drug Discovery; Mycobacterium Infections, Nontuberculous; Tuberculosis; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 36296540
DOI: 10.3390/molecules27206948 -
PloS One 2023Mycobacterium abscessus infections are relatively common in patients with cystic fibrosis and are clinically challenging, with frequent intrinsic resistance to...
Mycobacterium abscessus infections are relatively common in patients with cystic fibrosis and are clinically challenging, with frequent intrinsic resistance to antibiotics. Therapeutic treatment with bacteriophages offers some promise but faces many challenges including substantial variation in phage susceptibilities among clinical isolates, and the need to personalize therapies for individual patients. Many strains are not susceptible to any phages or are not efficiently killed by lytic phages, including all smooth colony morphotype strains tested to-date. Here, we analyze a set of new M. abscessus isolates for the genomic relationships, prophage content, spontaneous phage release, and phage susceptibilities. We find that prophages are common in these M. abscessus genomes, but some have unusual arrangements, including tandemly integrated prophages, internal duplications, and they participate in active exchange of polymorphic toxin-immunity cassettes secreted by ESX systems. Relatively few strains are efficiently infected by any mycobacteriophages, and the infection patterns do not reflect the overall phylogenetic relationships of the strains. Characterization of these strains and their phage susceptibility profiles will help to advance the broader application of phage therapies for NTM infections.
Topics: Humans; Bacteriophages; Prophages; Mycobacterium abscessus; Phylogeny; Genome; Mycobacterium Infections, Nontuberculous
PubMed: 36795728
DOI: 10.1371/journal.pone.0281769