Deciphering Microbial Regulation of Heterogeneity and Drug Adaptation with Meta-transcriptomics and Other System-Level Tools

Bacterial pathogens have evolved a diversity of adaptation mechanisms that enable them to survive under stresses including drug exposure. A key adaptive strategy is exerting bacterial control over molecular and phenotypic heterogeneity within the population, which enables the bacteria to tune bet-hedging and other survival adaptations under a broad spectrum of stress conditions. Therefore, a promising opportunity to inform the next generation of more durable and effective antimicrobial intervention strategies involves elucidating the mechanisms underlying the bacterial processes that promote adaptive heterogeneity and circumventing these processes. In this chapter, we will discuss different modalities of bacterial heterogeneity. We will describe what environmental sources stimulate the formation and modulation of heterogeneity, featuring sources from host–pathogen interactions and polymicrobial interactions. We will highlight molecular factors, both genetic and nongenetic, that regulate the extent and types of heterogeneity within a bacterial population. We will review the current understanding of how the responses that modulate heterogeneity can help the bacteria to survive and adapt to drug pressure. To showcase promising efforts in characterizing and intervening against heterogeneity and bacterial adaptation, we will highlight next-generation research tools, including meta-transcriptomics, functional genomic screening, and genome-scale modeling, that can enable multimodal and systems-level characterization of drug-adaptive heterogeneity and aid in identifying novel candidate targets for intervention. We will further discuss how strategic application of combinatorial treatments that include antibiotics, host-directed therapies, and bacteriophage therapies as an important therapeutic strategy that can specifically counter or exploit bacterial drug-adaptive processes and heterogeneity to improve treatment outcomes of recalcitrant infections.