Tigecycline Shows Promise Against Drug-Resistant Nontuberculous Mycobacteria, Review Finds

Nontuberculous mycobacteria, or NTM, are opportunistic environmental pathogens that have quietly become one of the most stubborn challenges in modern infectious disease medicine. Unlike their notorious relatives that cause tuberculosis and leprosy, these ubiquitous organisms primarily strike the lungs of people with pre-existing respiratory conditions, though they can also cause skin infections, lymphadenitis, and disseminated disease in immunocompromised patients. Now, a comprehensive review published in Molecular Biology Reports has synthesized evidence from 28 studies to map how these bacteria resist tigecycline, a glycylcycline antibiotic that has emerged as one of the few remaining options against multidrug-resistant isolates. The review, conducted by researchers at Fiocruz in Brazil, offers both encouragement and caution: tigecycline works remarkably well against rapidly growing species such as Mycobacterium abscessus, but its activity against slow-growing relatives like M. avium and M. kansasii remains disappointingly limited.

The clinical stakes are considerable. The World Health Organization does not publish a global prevalence report for NTM, so estimates come from national cohort studies and systematic reviews, and these consistently show rising incidence and prevalence over recent decades, with a particularly pronounced burden in low-income nations. The M. avium complex remains the predominant species in most countries. These bacteria thrive in humid environments, colonizing showers, hot tubs, thermal springs, and ventilation systems, and people typically acquire infection by inhaling contaminated aerosols. Their capacity to form biofilms allows them to colonize medical devices and water distribution systems, and infections have even followed tattoos, piercings, and cosmetic procedures. While person-to-person transmission is uncommon, evidence suggests potential transmission between cystic fibrosis patients and in specific healthcare settings, adding a troubling dimension to an already difficult problem.

Tigecycline itself is a derivative of minocycline and belongs to the glycylcycline class, engineered to overcome many of the mechanisms that render older tetracyclines ineffective. Its mechanism of action is elegant in its simplicity: the molecule binds to the 30S subunit of the bacterial ribosome, blocking the entry of aminoacyl-tRNA into the A site and thereby halting protein synthesis. Against Gram-positive and Gram-negative bacteria alike, and against certain mycobacteria, this broad-spectrum activity has made tigecycline a valuable last-resort agent. But mycobacteria are formidable adversaries. Their lipid-rich cell walls, packed with mycolic acids and studded with only sparse porin channels, form a permeability barrier that limits antibiotic penetration, and they deploy an arsenal of active resistance mechanisms on top of this passive defense.

The review’s authors searched Scopus, PubMed, the Virtual Health Library, SciELO, Web of Science, and LILACS between September and December 2025, screening 42 potentially relevant articles and ultimately including 28 in their analysis. The evidence they compiled paints a nuanced picture. Early studies reported consistently low minimum inhibitory concentrations, or MIC values, for tigecycline against the M. abscessus complex, with MIC50 values at or below 0.12 micrograms per milliliter and MIC90 values of 0.25 micrograms per milliliter in rapidly growing mycobacteria including M. abscessus, M. chelonae, and M. fortuitum. More recent work, however, has documented heterogeneity, with some clinical isolates showing resistance or reduced susceptibility despite the drug’s initially promising in vitro profile, suggesting that genetic determinants play a substantial role in modulating susceptibility.

One of the most striking findings concerns MabTetX, a flavin-dependent monooxygenase encoded by the gene MAB_1496c that serves as the principal tetracycline resistance determinant in M. abscessus. This enzyme degrades classical tetracyclines, and its expression increases in the presence of tetracycline and doxycycline. Crucially, however, tigecycline does not induce MabTetX expression and is far less affected by the enzyme’s activity, which explains why the drug retains activity against isolates resistant to older tetracyclines. This structural advantage, though, does not prevent resistance from emerging through entirely different adaptive pathways, a theme that runs throughout the review’s molecular analysis.

That adaptive machinery centers on WhiB7, a transcription factor that functions as the master regulator of the intrinsic antibiotic stress response in mycobacteria. When activated, WhiB7 induces a suite of resistance-associated genes including erm(41), eis2, hflX, and members of the ABCF family, promoting adaptive resistance to several antimicrobial classes. Experimental studies showed that deleting whiB7 significantly increases susceptibility to tigecycline, while its expression raises the MIC. The review also highlights the sigH-rshA axis: mutations in rshA, which encodes an anti-sigma factor, disrupt the interaction between RshA and the sigma factor SigH, leading to SigH overexpression and extensive transcriptional reprogramming characterized by reduced ribosomal protein synthesis, enhanced stress adaptation, and increased antibiotic tolerance. A spontaneous M. abscessus mutant carrying an rshA mutation exhibited tigecycline resistance, cross-resistance to imipenem, and a modest growth defect, and subsequent work linked the dysregulated stress response to decreased ribosomal gene expression and transient resistance induced by heat stress.

Efflux pumps add yet another layer of defense. Members of the MmpL family, particularly MmpL5, together with ABCF and Major Facilitator Superfamily transporters, actively export tigecycline from the bacterial cell, driven by ATP hydrolysis. Transcriptomic analyses demonstrated that just 24 hours of exposure to tigecycline significantly induces the expression of these efflux systems, reducing intracellular drug concentrations and limiting binding to the ribosomal target. Notably, many of these transporters appear to be regulated directly or indirectly by WhiB7, underscoring how tightly interconnected the resistance pathways are. Efflux pump inhibitors offer a tantalizing countermeasure: verapamil, the most extensively studied, has been shown to reduce the activity of multiple efflux pumps and potentially lower tigecycline MIC values in some isolates, while CCCP dissipates the proton motive force that powers proton-dependent pumps, and reserpine directly blocks MFS transporters. However, most evidence for these inhibitors comes from combinations with other antimicrobials such as bedaquiline, clofazimine, rifampicin, and macrolides, and their clinical application remains experimental.

In sharp contrast to the rapid growers, slow-growing species present a fundamentally different problem. M. avium, M. intracellulare, and M. kansasii consistently exhibit MIC values exceeding 4 micrograms per milliliter, with reported MIC50 and MIC90 values of at least 8 micrograms per milliliter in some studies. Here, reduced susceptibility appears rooted in intrinsic characteristics, particularly the highly lipid-rich, poorly permeable cell envelope and lower metabolic activity, rather than the adaptive regulatory mechanisms so extensively characterized in M. abscessus. A systematic review of 89 studies confirmed that tigecycline demonstrates greater activity against rapidly growing NTM, while evidence supporting its efficacy in slow-growing species remains limited. The review’s authors conclude that tigecycline is best positioned as a component of combination regimens for rapid-growing NTM, particularly multidrug-resistant isolates, and should rarely, if ever, be used as monotherapy given the growing recognition of adaptive resistance mechanisms.

Significant caveats temper these conclusions. Most available studies rely on in vitro susceptibility testing with relatively small collections of clinical isolates focused mainly on the M. abscessus complex, and substantial methodological variability in broth microdilution protocols, culture media, incubation periods, and isolate selection makes direct comparison across studies difficult. Isolates from different geographic regions may carry regional genetic diversity that further influences susceptibility profiles. Perhaps most critically, standardized clinical breakpoints for tigecycline have not yet been established, which restricts the translation of MIC data into clinical decision-making. Other proposed determinants, such as mutations in the gene MAB_3542c and in rpsA, have not been consistently reproduced, and biofilm formation’s contribution to tigecycline resistance remains poorly quantified.

Looking forward, the review’s authors call for multicenter studies with larger, geographically diverse isolate collections and standardized susceptibility testing protocols. Integrated genomic and transcriptomic approaches will be essential to identify novel resistance determinants and to determine whether the mechanisms described in M. abscessus are conserved across other NTM species. Establishing robust correlations between in vitro susceptibility, molecular mechanisms, and actual clinical outcomes will be critical for defining clinically relevant breakpoints and optimizing tigecycline-based regimens. For now, the message is one of cautious optimism: a drug once considered mainly for other resistant infections may become a cornerstone of therapy against some of the most treatment-refractory mycobacteria, provided clinicians deploy it wisely and researchers close the gaps that still separate laboratory promise from bedside certainty.

Subject of Research: Mechanisms and prevalence of tigecycline resistance in nontuberculous mycobacteria

Article Title: A review of tigecycline resistance in nontuberculous mycobacteria

Article References: Moura, C. D. S., da Silva, W. M. V., & Ramos, J. P. (2026). A review of tigecycline resistance in nontuberculous mycobacteria. Molecular Biology Reports, 53(1), Article 1637. https://doi.org/10.1007/s11033-026-12747-1

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12747-1

Keywords: tigecycline, nontuberculous mycobacteria, Mycobacterium abscessus, antimicrobial resistance, efflux pumps, WhiB7, MabTetX, SigH-RshA, minimum inhibitory concentration, glycylcyclines, combination therapy, drug-resistant bacteria