Neglected diseases of neglected populations: Thinking to reshape the determinants of health in Latin America and the Caribbean

BACKGROUND: People living in poverty throughout the developing world are heavily burdened with neglected communicable diseases and often marginalized by the health sector. These diseases are currently referred to as Neglected Diseases of Neglected Populations. The neglected diseases create social and financial burdens to the individual, the family, the community, and the nation. DISCUSSION: Numerous studies of successful individual interventions to manage communicable disease determinants in various types of communities have been published, but few have applied multiple interventions in an integrated, coordinated manner. We have identified a series of successful interventions and developed three hypothetical scenarios where such interventions could be applied in an integrated, multi-disease, inter-programmatic, and/or inter-sectoral approach for prevention and control of neglected diseases in three different populations: a slum, an indigenous community, and a city with a mix of populations. SUMMARY: The objective of this paper is to identify new opportunities to address neglected diseases, improve community health and promote sustainable development in neglected populations by highlighting examples of key risk and protective factors for neglected diseases which can be managed and implemented through multi-disease-based, integrated, inter-programmatic, and/or inter-sectoral approaches. Based on a literature review, analysis and development of scenarios we visualize how multiple interventions could manage multiple disease problems and propose these as possible strategies to be tested. We seek to stimulate intra- and inter-sectoral dialogue which will help in the construction of new strategies for neglected diseases (particularly for the parasitic diseases) which could benefit the poor and marginalized based on the principle of sustainability and understanding of key determinants of health, and lead to the establishment of pilot projects and activities which can contribute to the achievement of the Millennium Development Goals

An integrated network analysis reveals that nitric oxide reductase prevents metabolic cycling of nitric oxide by Pseudomonas aeruginosa

Nitric oxide (NO) is a chemical weapon within the arsenal of immune cells, but is also generated endogenously by different bacteria. Pseudomonas aeruginosa are pathogens that contain an NO-generating nitrite (NO2 ) reductase (NirS), and NO has been shown to influence their virulence. Interestingly, P. aeruginosa also contain NO dioxygenase (Fhp) and nitrate (NO3 (-)) reductases, which together with NirS provide the potential for NO to be metabolically cycled (NO -> NO3 (-)-> NO2 (-)-> NO). Deeper understanding of NO metabolism in P. aeruginosa will increase knowledge of its pathogenesis, and computational models have proven to be useful tools for the quantitative dissection of NO biochemical networks. Here we developed such a model for P. aeruginosa and confirmed its predictive accuracy with measurements of NO, O-2, NO2 (-), and NO3 (-) in mutant cultures devoid of Fhp or NorCB (NO reductase) activity. Using the model, we assessed whether NO was metabolically cycled in aerobic P. aeruginosa cultures. Calculated fluxes indicated a bottleneck at NO3 (-), which was relieved upon O-2 depletion. As cell growth depleted dissolved O-2 levels, NO3 (-) was converted to NO2 (-) at near-stoichiometric levels, whereas NO2 (-) consumption did not coincide with NO or NO3 (-) accumulation. Assimilatory NO2 reductase (NirBD) or NorCB activity could have prevented NO cycling, and experiments with Delta nirB,Delta nirS, and Delta norC showed that NorCB was responsible for loss of flux from the cycle. Collectively, this work provides a computational tool to analyze NO metabolism in P. aeruginosa, and establishes that P. aeruginosa use NorCB to prevent metabolic cycling of NO

Non-Monotonic Survival of Staphylococcus aureus with Respect to Ciprofloxacin Concentration Arises from Prophage-Dependent Killing of Persisters

Staphylococcus aureus is a notorious pathogen with a propensity to cause chronic, non-healing wounds. Bacterial persisters have been implicated in the recalcitrance of S. aureus infections, and this motivated us to examine the persistence of S. aureus to ciprofloxacin, a quinolone antibiotic. Upon treatment of exponential phase S. aureus with ciprofloxacin, we observed that survival was a non-monotonic function of ciprofloxacin concentration. Maximal killing occurred at 1 µg/mL ciprofloxacin, which corresponded to survival that was up to ~40-fold lower than that obtained with concentrations ≥ 5 µg/mL. Investigation of this phenomenon revealed that the non-monotonic response was associated with prophage induction, which facilitated killing of S. aureus persisters. Elimination of prophage induction with tetracycline was found to prevent cell lysis and persister killing. We anticipate that these findings may be useful for the design of quinolone treatments

The role of metabolism in bacterial persistence

Bacterial persisters are phenotypic variants with extraordinary tolerances toward antibiotics. Persister survival has been attributed to inhibition of essential cell functions during antibiotic stress, followed by reversal of the process and resumption of growth upon removal of the antibiotic. Metabolism plays a critical role in this process, since it participates in the entry, maintenance, and exit from the persister phenotype. Here, we review the experimental evidence that demonstrates the importance of metabolism to persistence, highlight the successes and potential for targeting metabolism in the search for anti-persister therapies, and discuss the current methods and challenges to understand persister physiology