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The impact of respiratory coinfections in COVID-19 is still not well understood despite the growing evidence that consider coinfections greater than expected. A total of 295 patients older than 18 years of age, hospitalized with a confirmed diagnosis of moderate/severe pneumonia due to SARS-CoV-2 infection (according to definitions established by the Ministry of Health of Peru) were enrolled during the study period. A coinfection with one or more respiratory pathogens was detected in 154 (52.2%) patients at hospital admission. The most common coinfections were Mycoplasma pneumoniae (28.1%), Chlamydia pneumoniae (8.8%) and with both bacteria (11.5%); followed by Adenovirus (1.7%), Mycoplasma pneumoniae/Adenovirus (0.7%), Chlamydia pneumoniae/Adenovirus (0.7%), RSV-B/Chlamydia pneumoniae (0.3%) and Mycoplasma pneumoniae/Chlamydia pneumoniae/Adenovirus (0.3%). Expectoration was less frequent in coinfected individuals compared to non-coinfected (5.8% vs. 12.8%). Sepsis was more frequent among coinfected patients than non-coinfected individuals (33.1% vs. 20.6%) and 41% of the patients who received macrolides empirically were PCR-positive for Mycoplasma pneumoniae and Chlamydia pneumoniae. / National Research Foundation of Korea / Revisión por pares

Pseudomonas aeruginosa is a Gram-negative pathogen that forms biofilms, which increase tolerance to antibiotics. Biofilms are dense, surfaceassociated communities of bacteria that grow in a self-produced matrix of polysaccharides, proteins, and extracellular DNA (eDNA). Sub-minimal inhibitory concentration (sub-MIC) levels of antibiotics induce the formation of biofilms, indicating a potential role in response to antibiotic stress. However, the mechanisms behind sub-MIC antibiotic-induced biofilm formation are unknown. We show that treatment with sub-MIC levels of cefixime (cephalosporin), carbenicillin (β-lactam), tobramycin (aminoglycoside), chloramphenicol (chloramphenicol), thiostrepton (thiopeptide), novobiocin (aminocoumarin), ciprofloxacin (fluoroquinolone), or trimethoprim (antifolate) induces biofilm formation, with maximal induction at ~ ¼ to ½ MIC. We demonstrate that addition of exogenous eDNA or cell lysate does not stimulate biofilm formation to the same extent as antibiotics, suggesting that the release of common goods by antibiotic action does not solely drive the biofilm response. We show that increased biofilm formation upon antibiotic exposure requires the outer membrane porin OprF and the extracytoplasmic function sigma factor SigX. Through transposon mutant screening and deletion studies, we found that OprF is important for biofilm induction, as mutants lacking this protein did not form increased biofilm when exposed to sub-MIC antibiotics. OprF expression is v controlled by SigX, and its loss increases SigX activity. Loss of SigX also prevents biofilm induction by sub-MIC antibiotics. Together, these results show that antibiotic-induced biofilm formation may constitute a type of stress response. This response may be useful to screen for new antibiotics due to its ability to reveal antibiotic activity at concentrations below the MIC. Further study of this response may also provide targets for adjuvant therapies that reduce biofilm formation in P. aeruginosa infections and increase the efficacy of current antibiotics. / Thesis / Master of Science (MSc) / Pseudomonas aeruginosa is a bacterium that causes illness in patients with compromised immune systems, like patients with cystic fibrosis. This bacterium forms biofilms, which are dense groups that stick to surfaces within a protective slime that contains proteins, sugars, and DNA. Biofilms make the bacteria harder to treat with antibiotics. If the bacteria are treated with low levels of antibiotics, they respond by forming more biofilm but how this happens is unknown. We showed that adding DNA does not increase biofilm formation, while adding dead cell debris only causes a small increase. By testing a library of mutant bacteria, we found that they need two genes, oprF and sigX, to form more biofilm when they are treated with low levels of antibiotic. By studying how bacteria respond to low levels of antibiotics, we can find ways to identify new antibiotics and to make our current antibiotics work better.

Antimicrobial resistance is a human health issue that demands development of new antibiotics with unique mechanisms of action to combat antibiotic failure in the clinic. Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a particular resistant pathogen associated with high levels of incidence and mortality. Isolation and structural elucidation of the antibiotic natural products armeniaspirols A-C was first reported in 2012 by Sanofi. Armeniaspirol possess an unprecedented scaffold and novel multiple mechanisms of action. For these reasons the armeniaspirols were an ideal scaffold to investigate for the development of antibiotics effective against current resistant pathogens. A series of focused derivatives were synthesized and evaluated for antibiotic activity against clinically relevant pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Replacement of the N-methyl with N-hexyl and various N-benzyl substituents lead to a substantial increase in antibiotic activity and potency for inhibition of both ClpYQ and ClpXP, the intracellular targets of armeniaspirol. Armeniaspirol is also known to disrupt the proton motive force (PMF) in bacteria, though initial work by the Brönstrup lab suggested this was via shuttling of protons across the membrane. With a library of analogues in hand from our previous study, we sought to characterize their disruption of the PMF. Using a voltage sensitive dye-based assay and checkerboard synergy-based assay we demonstrated that armeniaspirols disrupt the proton motive force by dissipating the electrical potential (ΔΨ) of the PMF, correcting the previous literature, which suggested they disrupted the transmembrane proton gradient (ΔpH). Lastly, our efforts toward the total synthesis of armeniaspirol A using an oxidative chlorination transformation led to a constitutional isomer of armeniaspirol by an unexpected Lewis acid mediated rearrangement in the penultimate step. We characterized the scope of carbonyl derivatives that could undergo successful oxidation generating the key α,β-dichloro-α,β-unsaturated lactam of the armeniaspirol scaffold. Our work led to a mechanistic study demonstrating how simple ketones undergo decomposition via acylium ion formation whereas esters and amides are effectively oxidized to the desired product. Overall, the research presented here lays the foundation for the future work to confirm safety, efficacy, and toxicity of the armeniaspirols and to synthesize new analogues with improved drug like characteristics. In addition, this thesis previews an evolution-based link between armeniaspirol and its biosynthetic precursor that suggests mid- to late-stage biosynthetic intermediates are likely to possess biological activity but via a different mechanism of action as compared to the parent natural products. Furthermore, this analysis suggests that the intermediate is likely to synergize with the natural product, increasing the fitness of the producing organism as the pathway evolves.

Chronic obstructive pulmonary disease (COPD) is an illness characterized by progressive respiratory symptoms and frequent exacerbations. Acute exacerbations of COPD (AECOPD) are mostly treated in the outpatient setting and the use of antibiotics for this patient population remains controversial. This thesis aimed to explore the role of antibiotics in the outpatient management of AECOPD through two studies. The first study was a systematic review of randomized controlled trials examining the impact of antibiotics on the outcome of treatment failure in outpatients with AECOPD. Meta-analysis was conducted using both frequentist random effects and Bayesian analyses. The second study was a secondary analysis of a prospective cohort of patients with AECOPD discharged from the emergency department. The association between antibiotic treatment and the outcome of rehospitalization within 14 days of discharge was examined using logistic regression and propensity score matched analyses. In the systematic review and meta-analysis, both frequentist random effects and Bayesian analyses revealed a high likelihood of benefit for antibiotics. In the secondary analysis, there was no association between treatment with antibiotics and rehospitalization however due to a small sample size and a low event rate, there was considerable risk of Type II error. Overall, when considering the results of these two studies in the context of previous literature, treatment with antibiotics likely provides a modest benefit in the outpatient management of AECOPD.

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