From microbial gene essentiality to novel antimicrobial drug targets.

Background: Bacterial respiratory tract infections, mainly caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are among the leading causes of global mortality and morbidity. Increased resistance of these pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials.

Result: Here, we report a proof of concept study for the reliable identification of potential drug targets in these human respiratory pathogens by combining high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics.

Genome-wide identification of genes essential for the survival of Streptococcus pneumoniae in human saliva.

Since Streptococcus pneumoniae transmits through droplet spread, this respiratory tract pathogen may be able to survive in saliva. Here, we show that saliva supports survival of clinically relevant S. pneumoniae strains for more than 24 h in a capsule-independent manner.

Combination of pantothenamides with vanin inhibitors as a novel antibiotic strategy against gram-positive bacteria.

The emergence of resistance against current antibiotics calls for the development of new compounds to treat infectious diseases. Synthetic pantothenamides are pantothenate analogs that possess broad-spectrum antibacterial activity in vitro in minimal media. Pantothenamides were shown to be substrates of the bacterial coenzyme A (CoA) biosynthetic pathway, causing cellular CoA depletion and interference with fatty acid synthesis.

A single amino acid substitution in the MurF UDP-MurNAc-pentapeptide synthetase renders Streptococcus pneumoniae dependent on CO2 and temperature.

The respiratory tract pathogen Streptococcus pneumoniae encounters different levels of environmental CO2 during transmission, host colonization and disease. About 8% of all pneumococcal isolates are capnophiles that require CO2 -enriched growth conditions. The underlying molecular mechanism for caphnophilic behaviour, as well as its biological function is unknown.

Nontypeable Haemophilus influenzae carbonic anhydrase is important for environmental and intracellular survival.

Nontypeable Haemophilus influenzae (NTHi) is one of the leading causes of noninvasive mucosal infections, such as otitis media, sinusitis, and conjunctivitis. During its life cycle, NTHi is exposed to different CO2 levels, which vary from ∼0.04% in ambient air during transmission to a new host to over 5% in the respiratory tract and tissues of the human host during colonization and disease.