Current Opinion in Microbiology

Antimicrobial susceptibility testing is the cornerstone of antibiotic treatments. Yet, active drugs are frequently unsuccessful in vivo and most clinical trials investigating antibiotics fail. So far, bacterial survival strategies, other than drug resistance, have been largely ignored. As such, drug tolerance and persisters, allowing bacterial populations to survive during antibiotic treatments, could fill a gap in antibiotic susceptibility testing. Therefore, it remains critical to establish robust and scalable bacterial viability measures and to define the clinical relevance of bacterial survivors across various bacterial infections...

The approval of the first-in-class antibacterial bedaquiline for tuberculosis marks a breakthrough in antituberculosis drug development. The drug inhibits mycobacterial respiration and represents the validation of a wholly different metabolic process as a druggable target space. In this review, we discuss the advances in the development of mycobacterial respiratory inhibitors, as well as the potential of applying this strategy to other pathogens. The non-fermentative nature of mycobacteria explains their vulnerability to respiration inhibition, and we caution that this strategy may not be equally effective in other organisms...

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Due to recent discovery efforts, over 100 immune systems encoded by bacteria that antagonize bacteriophage (phage) replication have been uncovered. These systems employ direct and indirect mechanisms to detect phage infection and activate bacterial immunity. The most well-studied mechanisms are direct detection and activation by phage-associated molecular patterns (PhAMPs), such as phage DNA and RNA sequences, and expressed phage proteins that directly activate abortive infection systems. Phage effectors may also inhibit host processes and, therefore, indirectly activate immunity...

A resurgence of interest in the pathways that bacteria use to protect against their viruses (i.e. phages) has led to the discovery of dozens of new antiphage defenses. Given the sheer abundance and diversity of phages - the ever-evolving targets of immunity - it is not surprising that these newly described defenses are also remarkably diverse. However, as their mechanisms slowly come into focus, some common strategies and themes are also beginning to emerge. This review highlights recurring and emerging themes in the mechanisms of innate immunity in bacteria and archaea, with an emphasis on recently described systems that have undergone more thorough mechanistic characterization...

Cells across domains of life have dedicated pathways to sense and respond to DNA damage. These responses are broadly termed as DNA damage responses (DDRs). In bacteria, the best studied DDR is the Save our Soul (SOS) response. More recently, several SOS-independent DDRs have also been discovered. Studies further report diversity in the types of repair proteins present across bacterial species as well as differences in their mechanisms of action. Although the primary function of DDRs is preservation of genome integrity, the diverse organization, conservation, and function of bacterial DDRs raises important questions about how genome error correction mechanisms could influence or be influenced by the genomes that encode them...

Fever is a part of the human innate immune response that contributes to limiting microbial growth and development in many infectious diseases. For the parasite Plasmodium falciparum, survival of febrile temperatures is crucial for its successful propagation in human populations as well as a fundamental aspect of malaria pathogenesis. This review discusses recent insights into the biological complexity of the malaria parasite's heat-shock response, which involves many cellular compartments and essential metabolic processes to alleviate oxidative stress and accumulation of damaged and unfolded proteins...

Temperate phages are pervasive in nature, existing within bacterial cells in a form known as prophages. In this state, survival of the phage is intricately tied to the survival of the bacterial host. As a result, prophages often encode genes that increase bacterial fitness. One important way to increase survival is to provide defense against competing phages. Recent work reviewed here reveals that prophages provide a diverse and robust reservoir of antiphage defense systems that likely play a major role in bacterial-phage dynamics...

The Toll/interleukin-1 receptor (TIR) domain is found in animal, plant, and bacterial immune systems. It was first described as a protein-protein interaction module mediating signalling downstream of the Toll-like receptor and interleukin-1 receptor families in animals. However, studies of the pro-neurodegenerative protein sterile alpha and TIR motif containing 1, plant immune receptors, and many bacterial TIR domain-containing proteins revealed that TIR domains have enzymatic activities and can produce diverse nucleotide products using nicotinamide adenine dinucleotide (NAD+ ) or nucleic acids as substrates...

Recent discoveries of basal extracellular Rickettsiales have illuminated divergent evolutionary paths to host dependency in later-evolving lineages. Family Rickettsiaceae, primarily comprised of numerous protist- and invertebrate-associated species, also includes human pathogens from two genera, Orientia and Rickettsia. Once considered sister taxa, these bacteria form distinct lineages with newly appreciated lifestyles and morphological traits. Contrasting other rickettsial human pathogens in Family Anaplasmataceae, Orientia and Rickettsia species do not reside in host-derived vacuoles and lack glycolytic potential...

Viruses are locked in an evolutionary arms race with their hosts. What ultimately determines viral evolvability, or capacity for adaptive evolution, is their ability to efficiently explore and expand sequence space while under the selective regime imposed by their ecology, which includes innate and adaptive host defenses. Viral genomes have significantly higher evolutionary rates than their host counterparts and should have advantages relative to their slower-evolving hosts. However, functional constraints on virus evolutionary landscapes along with the modularity and mutational tolerance of host defense proteins may help offset the advantage conferred to viruses by high evolutionary rates...

There is growing knowledge that the maternal gut microbiome undergoes substantial changes during pregnancy. However, despite the recognition that the maternal gut microbiome influences maternal and infant health, we still have a limited understanding of the clinical and environmental factors that can impact the maternal gut microbiome during pregnancy and the consequences of these changes. Here, we review the current body of knowledge about factors shaping the maternal gut microbiome during pregnancy and its role in the development of pregnancy complications and infant health...

Bacteriophages (phages) are viruses that specifically infect bacteria. These viruses were discovered a century ago and have been used as a model system in microbial genetics and molecular biology. In order to survive, bacteria have to quickly adapt to phage challenges in their natural settings. In turn, phages continuously develop/evolve mechanisms for battling host defenses. A deeper understanding of the arms race between bacteria and phages is essential for the rational design of phage-based prophylaxis and therapies to prevent and treat bacterial infections...

The gut microbiota is now recognized to be a key driver of mucosal inflammation in inflammatory bowel disease (IBD). Robust functional and compositional alterations of the gut microbiota have been described in IBD with a reduction in bacterial diversity, a reduction in some anti-inflammatory anaerobic bacteria, and an increase in bacteria with pro-inflammatory potential. However, despite 15 years of active research, therapeutical applications are still lacking. Recent studies have shed new light on how targeting the gut microbiota can be beneficial in IBD with fecal microbiota transplantation, next-generation probiotics, and phage therapy...

Metabolic interactions are fundamental to the assembly and functioning of microbiomes, including those of plants. However, disentangling the molecular basis of these interactions and their specific roles remains a major challenge. Here, we review recent applications of experimental and computational methods toward the elucidation of metabolic interactions in plant-associated microbiomes. We highlight studies that span various scales of taxonomic and environmental complexity, including those that test interaction outcomes in vitro and in planta by deconstructing microbial communities...

Intracellular immune complexes known as inflammasomes sense breaches of cytosolic sanctity. Inflammasomes promote downstream proinflammatory events, including interleukin-1 (IL-1) family cytokine release and pyroptotic cell death. The nucleotide-binding leucine-rich repeat family, apoptosis inhibitory protein/nucleotide-binding leucine-rich repeat family, caspase recruitment domain (CARD) domain-containing protein 4 (NAIP/NLRC4) inflammasome is involved in a range of pathogenic and protective inflammatory processes in mammalian hosts...

The formation of lateral microdomains is emerging as a central organizing principle in bacterial membranes. These microdomains are targets of antibiotic development and have the potential to enhance natural product synthesis, but the rules governing their assembly are unclear. Previous studies have suggested that microdomain formation is promoted by lipid phase separation, particularly by cardiolipin (CL) and isoprenoid lipids, and there is strong evidence that CL biosynthesis is required for recruitment of membrane proteins to cell poles and division sites...

Bacteria are single-celled organisms, but the survival of microbial communities relies on complex dynamics at the molecular, cellular, and ecosystem scales. Antibiotic resistance, in particular, is not just a property of individual bacteria or even single-strain populations, but depends heavily on the community context. Collective community dynamics can lead to counterintuitive eco-evolutionary effects like survival of less resistant bacterial populations, slowing of resistance evolution, or population collapse, yet these surprising behaviors are often captured by simple mathematical models...

The increasing prevalence of infections caused by antibiotic-resistant bacteria is a global healthcare crisis. Understanding the spread of resistance is predicated on the surveillance of antibiotic resistance genes within an environment. Bioinformatics and artificial intelligence (AI) methods applied to metagenomic sequencing data offer the capacity to detect known and infer yet-unknown resistance mechanisms, and predict future outbreaks of antibiotic-resistant infections. Machine learning methods, in particular, could revive the waning antibiotic discovery pipeline by helping to predict the molecular structure and function of antibiotic resistance compounds, and optimising their interactions with target proteins...

Multicellular behavior benefits seemingly simple organisms such as bacteria, by improving nutrient uptake, resistance to stresses, or by providing advantages in predatory interactions. Several recent studies have shown that this also extends to the defense against bacteriophages, which are omnipresent in almost all habitats. In this review, we summarize strategies conferring protection against phage infection at the multicellular level, covering secretion of small antiphage molecules or membrane vesicles, the role of quorum sensing in phage defense, the development of transient phage resistance, and the impact of biofilm components and architecture...