Novel Synergies and Isolate Specificities in the Drug Interaction Landscape of Mycobacterium abscessus
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Novel Synergies and Isolate Specificities in the Drug Interaction Landscape of Mycobacterium abscessus. / Van, Nhi; Degefu, Yonatan N; Leus, Pathricia A; Larkins-Ford, Jonah; Klickstein, Jacob; Maurer, Florian P; Stone, David; Poonawala, Husain; Thorpe, Cheleste M; Smith, Trever C; Aldridge, Bree B.
In: ANTIMICROB AGENTS CH, Vol. 67, No. 7, 18.07.2023, p. e00090-23.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Novel Synergies and Isolate Specificities in the Drug Interaction Landscape of Mycobacterium abscessus
AU - Van, Nhi
AU - Degefu, Yonatan N
AU - Leus, Pathricia A
AU - Larkins-Ford, Jonah
AU - Klickstein, Jacob
AU - Maurer, Florian P
AU - Stone, David
AU - Poonawala, Husain
AU - Thorpe, Cheleste M
AU - Smith, Trever C
AU - Aldridge, Bree B
PY - 2023/7/18
Y1 - 2023/7/18
N2 - Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treating M. abscessus infections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotics lacking efficacy data. We systematically measured drug combinations in M. abscessus to establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured 191 pairwise drug combination effects among 22 antibacterials and identified 71 synergistic pairs, 54 antagonistic pairs, and 66 potentiator-antibiotic pairs. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in the lab reference strain ATCC 19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies for M. abscessus is the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.
AB - Mycobacterium abscessus infections are difficult to treat and are often considered untreatable without tissue resection. Due to the intrinsic drug-resistant nature of the bacteria, combination therapy of three or more antibiotics is recommended. A major challenge in treating M. abscessus infections is the absence of a universal combination therapy with satisfying clinical success rates, leaving clinicians to treat infections using antibiotics lacking efficacy data. We systematically measured drug combinations in M. abscessus to establish a resource of drug interaction data and identify patterns of synergy to help design optimized combination therapies. We measured 191 pairwise drug combination effects among 22 antibacterials and identified 71 synergistic pairs, 54 antagonistic pairs, and 66 potentiator-antibiotic pairs. We found that commonly used drug combinations in the clinic, such as azithromycin and amikacin, are antagonistic in the lab reference strain ATCC 19977, whereas novel combinations, such as azithromycin and rifampicin, are synergistic. Another challenge in developing universally effective multidrug therapies for M. abscessus is the significant variation in drug response between isolates. We measured drug interactions in a focused set of 36 drug pairs across a small panel of clinical isolates with rough and smooth morphotypes. We observed strain-dependent drug interactions that cannot be predicted from single-drug susceptibility profiles or known drug mechanisms of action. Our study demonstrates the immense potential to identify synergistic drug combinations in the vast drug combination space and emphasizes the importance of strain-specific combination measurements for designing improved therapeutic interventions.
KW - Humans
KW - Mycobacterium abscessus
KW - Azithromycin/pharmacology
KW - Anti-Bacterial Agents/pharmacology
KW - Amikacin/pharmacology
KW - Mycobacterium Infections, Nontuberculous/drug therapy
KW - Drug Interactions
KW - Microbial Sensitivity Tests
U2 - 10.1128/aac.00090-23
DO - 10.1128/aac.00090-23
M3 - SCORING: Journal article
C2 - 37278639
VL - 67
SP - e00090-23
JO - ANTIMICROB AGENTS CH
JF - ANTIMICROB AGENTS CH
SN - 0066-4804
IS - 7
ER -