ABSTRACT The success of Mycobacterium tuberculosis as a human pathogen is due in part to its ability to survive stress conditions, such as hypoxia or nutrient deprivation, by entering nongrowing states. In these low-metabolism states, M. tuberculosis can tolerate antibiotics and develop genetically encoded antibiotic resistance, making its metabolic adaptation to stress crucial for survival. Numerous bacteria, including M. tuberculosis , have been shown to reduce their rates of mRNA degradation under growth limitation and stress. While the existence of this response appears to be conserved across species, the underlying bacterial mRNA stabilization mechanisms remain unknown. To better understand the biology of nongrowing mycobacteria, we sought to identify the mechanistic basis of mRNA stabilization in the nonpathogenic model Mycobacterium smegmatis . We found that mRNA half-life was responsive to energy stress, with carbon starvation and hypoxia causing global mRNA stabilization. This global stabilization was rapidly reversed when hypoxia-adapted cultures were reexposed to oxygen, even in the absence of new transcription. The stringent response and RNase levels did not explain mRNA stabilization, nor did transcript abundance. This led us to hypothesize that metabolic changes during growth cessation impact the activities of degradation proteins, increasing mRNA stability. Indeed, bedaquiline and isoniazid, two drugs with opposing effects on cellular energy status, had opposite effects on mRNA half-lives in growth-arrested cells. Taken together, our results indicate that mRNA stability in mycobacteria is not directly regulated by growth status but rather is dependent on the status of energy metabolism. IMPORTANCE The logistics of tuberculosis therapy are difficult, requiring multiple drugs for many months. Mycobacterium tuberculosis survives in part by entering nongrowing states in which it is metabolically less active and thus less susceptible to antibiotics. Basic knowledge on how M. tuberculosis survives during these low-metabolism states is incomplete, and we hypothesize that optimized energy resource management is important. Here, we report that slowed mRNA turnover is a common feature of mycobacteria under energy stress but is not dependent on the mechanisms that have generally been postulated in the literature. Finally, we found that mRNA stability and growth status can be decoupled by a drug that causes growth arrest but increases metabolic activity, indicating that mRNA stability responds to metabolic status rather than to growth rate per se . Our findings suggest a need to reorient studies of global mRNA stabilization to identify novel mechanisms that are presumably responsible.
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Modulation of antibiotic effects on microbial communities by resource competition
Antibiotic treatment significantly impacts the human gut microbiota, but quantitative understanding of how antibiotics affect community diversity is lacking. Here, we build on classical ecological models of resource competition to investigate community responses to species-specific death rates, as induced by antibiotic activity or other growth-inhibiting factors such as bacteriophages. Our analyses highlight the complex dependence of species coexistence that can arise from the interplay of resource competition and antibiotic activity, independent of other biological mechanisms. In particular, we identify resource competition structures that cause richness to depend on the order of sequential application of antibiotics (non-transitivity), and the emergence of synergistic and antagonistic effects under simultaneous application of multiple antibiotics (non-additivity). These complex behaviors can be prevalent, especially when generalist consumers are targeted. Communities can be prone to either synergism or antagonism, but typically not both, and antagonism is more common. Furthermore, we identify a striking overlap in competition structures that lead to non-transitivity during antibiotic sequences and those that lead to non-additivity during antibiotic combination. In sum, our results establish a broadly applicable framework for predicting microbial community dynamics under deleterious perturbations.
more » « less- NSF-PAR ID:
- 10409279
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Nature Communications
- Volume:
- 14
- Issue:
- 1
- ISSN:
- 2041-1723
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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