Glby, Encoded by
            <i>MAB_3167c</i>
            , Is Required for
            <i>In Vivo</i>
            Growth of Mycobacteroides abscessus and Exhibits Mild β-Lactamase Activity

Galanis, Christos; Maggioncalda, Emily C.; Kumar, Pankaj; Lamichhane, Gyanu

doi:10.1128/jb.00046-22

Cited by 4 publications

(5 citation statements)

References 70 publications

(91 reference statements)

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“…The method for constructing M. abscessus subsp. abscessus gene-deletion mutants is well established [32][33][34]. Further studies are needed to determine the virulence factors harbored by the M. abscessus subsp.…”

Section: Plos Onementioning

confidence: 99%

Quantitative evaluation of Mycobacterium abscessus clinical isolate virulence using a silkworm infection model

Matsumoto

Fukano²,

Hasegawa³

et al. 2022

PLoS ONE

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Mycobacterium abscessus causes chronic skin infections, lung diseases, and systemic or disseminated infections. Here we investigated whether the virulence of M. abscessus clinical isolates could be evaluated by calculating the median lethal dose (LD50) in a silkworm infection model. M. abscessus subsp. abscessus cells were injected into the silkworm hemolymph. When reared at 37˚C, the silkworms died within 2 days post-infection with M. abscessus subsp. abscessus. Viable cell numbers of M. abscessus increased in the hemolymph of silkworms injected with M. abscessus. Silkworms were not killed by injections with heat-killed M. abscessus cells. The administration of clarithromycin, an antibacterial drug used to treat the infection in humans, prolonged the survival time of silkworms injected with M. abscessus. The LD50 values of 7 clinical isolates in the silkworm infection model were differed by up to 9-fold. The Mb-17 isolate, which was identified as a virulent strain in the silkworm infection model, induced more detachment of human THP-1-derived macrophages during infection than the Mb-10 isolate. These findings suggest that the silkworm M. abscessus infection model can be used to quantitatively evaluate the virulence of M. abscessus clinical isolates in a short time period.

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Section: Plos Onementioning

confidence: 99%

Quantitative evaluation of Mycobacterium abscessus clinical isolate virulence using a silkworm infection model

Matsumoto

Fukano²,

Hasegawa³

et al. 2022

PLoS ONE

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“…D,D-transpeptidases play a pivotal role in the synthesis of peptidoglycan, whereas D,D-carboxypeptidases are responsible for catalyzing the removal of terminal amino acids from peptidoglycan sidechains. Several essential PBPs, including PBP-lipo ( MAB _3167 c), PBP B ( MAB _2000), DacB1, and DDC, were investigated, revealing that their “knockout” resulted in a synergistic growth-inhibition effect ( 8 – 10 ).…”

Section: Introductionmentioning

confidence: 99%

Synergistic effects of sulopenem in combination with cefuroxime or durlobactam against Mycobacterium abscessus

Dousa,

Shin,

Kurz

et al. 2024

mBio

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Mycobacterium abscessus ( Mab ) affects patients with immunosuppression or underlying structural lung diseases such as cystic fibrosis (CF). Additionally, Mab poses clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual β-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with β-lactamase inhibitors [BLIs—avibactam (AVI) or durlobactam (DUR)]. The sulopenem-CXM combination yielded low minimum inhibitory concentration (MIC) values for 54 clinical Mab isolates and ATCC19977 (MIC 50 and MIC 90 ≤0.25 µg/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding ~1.5 Log 10 CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in an additional reduction of CFUs (~3 Log 10 for sulopenem-CXM and AVI and ~4 Log 10 for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (Ldts; Ldt Mab1 –Ldt Mab4 ), penicillin-binding-protein B (PBP B), and D,D-carboxypeptidase (DDC). Acyl complexes, identified via mass spectrometry analysis, demonstrated the binding of sulopenem with Ldt Mab2 –Ldt Mab4 , DDC, and PBP B and CXM with Ldt Mab2 and PBP B. Molecular docking and mass spectrometry data suggest the formation of a covalent adduct between sulopenem and Ldt Mab2 after the nucleophilic attack of the cysteine residue at the β-lactam carbonyl carbon, leading to the cleavage of the β-lactam ring and the establishment of a thioester bond linking the Ldt Mab2 with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLIs. These findings potentially broaden the selection of oral therapeutic agents to combat Mab . IMPORTANCE Treating infections from Mycobacterium abscessus (Mab), particularly those resistant to common antibiotics like macrolides, is notoriously difficult, akin to a never-ending struggle for healthcare providers. The rate of treatment failure is even higher than that seen with multidrug-resistant tuberculosis. The role of combination β-lactams in inhibiting L,D-transpeptidation, the major peptidoglycan crosslink reaction in Mab, is an area of intense investigation, and clinicians have utilized this approach in the treatment of macrolide-resistant Mab, with reports showing clinical success. In our study, we found that cefuroxime and sulopenem, when used together, display a significant synergistic effect. If this promising result seen in lab settings, translates well into real-world clinical effectiveness, it could revolutionize current treatment methods. This combination could either replace the need for more complex intravenous medications or serve as a “step down” to an oral medication regimen. Such a shift would be much easier for patients to manage, enhancing their comfort and likelihood of sticking to the treatment plan, which could lead to better outcomes in tackling these tough infections. Our research delved into how these drugs inhibit cell wall synthesis, examined time-kill data and binding studies, and provided a scientific basis for the observed synergy in cell-based assays.

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“…We assessed the efficacies of the above-mentioned antibiotics in combination with omadacycline against a reference strain of M. abscessus (ATCC 19977) in a mouse model of pulmonary M. abscessus disease ( 32 ). Using this model, we have evaluated efficacies of single and dual antibiotics against M. abscessus ( 20 , 33 , 34 ) and growth kinetics of M. abscessus in the lungs of mice ( 35 ). Appropriate single-drug and no-drug control comparators were also included.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Omadacycline-Containing Regimen in a Mouse Model of Pulmonary Mycobacteroides abscessus Disease

Rimal

Nicklas

Panthi

et al. 2023

mSphere

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Glby, Encoded by MAB_3167c , Is Required for In Vivo Growth of Mycobacteroides abscessus and Exhibits Mild β-Lactamase Activity

Cited by 4 publications

References 70 publications

Quantitative evaluation of Mycobacterium abscessus clinical isolate virulence using a silkworm infection model

Quantitative evaluation of Mycobacterium abscessus clinical isolate virulence using a silkworm infection model

Synergistic effects of sulopenem in combination with cefuroxime or durlobactam against Mycobacterium abscessus

Efficacy of Omadacycline-Containing Regimen in a Mouse Model of Pulmonary Mycobacteroides abscessus Disease

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