The ever-increasing incidence of drug-resistant Mycobacterium tuberculosis infections has invigorated the focus on the discovery and development of novel treatment options. The discovery and investigation of essential mycobacterial targets is of utmost importance. In addition to the discovery of novel targets, focusing on non-lethal pathways and the use of host-directed therapies has gained interest. These adjunctive treatment options could not only lead to increased antibiotic susceptibility of Mycobacterium tuberculosis, but also have the potential to avoid the emergence of drug resistance. Host-directed therapies, on the other hand, can also reduce the associated lung pathology and improve disease outcome. This review will provide an outline of recent opportunities.

Streptococcus pneumoniae is the leading cause of bacterial pneumonia. Infection is linked to high morbidity and mortality rates and antibiotic resistance within this pathogen is on the rise. Therefore, there is a need for novel antimicrobial therapies. To lower the time and costs of the drug discovery process, alternative in vivo models should be considered. As such, Galleria mellonella larvae can be of great value. The larval immunity consisting of several types of haemocytes is remarkably similar to the human innate immune system. Furthermore, these larvae don’t require specific housing, are cheap and are easy to handle. In this study, the use of a G. mellonella infection model to study early pneumococcal infections and treatment is proposed. Firstly, the fitness of this model to study pneumococcal virulence factors is confirmed using streptococcal strains TIGR4, ATCC ® 49619, D39 and its capsule-deficient counterpart R6 at different inoculum sizes. The streptococcal polysaccharide capsule is considered the most important virulence factor without which streptococci are unable to sustain an in vivo infection. Kaplan–Meier survival curves showed indeed a higher larval survival after infection with streptococcal strain R6 compared to strain D39. Then, the infection was characterized by determining the number of haemocytes, production of oxygen free radicals and bacterial burden at several time points during the course of infection. Lastly, treatment of infected larvae with the standard antibiotics amoxicillin and moxifloxacin was evaluated. Treatment has proven to have a positive outcome on the course of infection, depending on the administered dosage. These data imply that G. mellonella larvae can be used to evaluate antimicrobial therapies against S. pneumoniae , apart from using the larval model to study streptococcal properties. The in-depth knowledge acquired regarding this model, makes it more suitable for use in future research.

Streptococcus pneumoniae, the most common cause of bacterial pneumonia, has developed a wide range of virulence factors to evade the immune system of which the polysaccharide capsule is the most important one. Formation of this capsule is dependent on the cps gene locus, but also involves other genes-like galU. The pyrophosphorylase encoded by galU plays a role in the UDP-glucose metabolism of prokaryotes and is required for the biosynthesis of capsular polysaccharides. In this paper, the effect of a galU mutation leading to a dysfunctional UDP-glucose pyrophosphorylase (UDPG:PP) on in vitro biofilm biomass, adherence to lung epithelial cells and macrophage phagocytosis is studied. Last, in vivo virulence using a Galleria mellonella model has been studied. We show that the mutation improves streptococcal adherence to epithelial cells and macrophage phagocytosis in vitro, while there is no definitive correlation on biofilm formation between parent and mutant strains. Moreover, in vivo virulence is attenuated for all mutated strains. Together, these results demonstrate that a galU mutation in S. pneumoniae influences host cell interactions in vitro and in vivo and can strongly influence the outcome of a streptococcal infection. As such, UDPG:PP is worth investigating further as a potential drug target.

International audienceWe report the design and synthesis of a series of non-nucleoside MtbTMPK inhibitors (1-14) based on the gram-positive bacterial TMPK inhibitor hit compound 1. A practical synthesis was developed to access these analogues. Several compounds show promising MtbTMPK inhibitory potency and allow the establishment of a structure-activity relationship, which is helpful for further optimization

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