Processes 2019, 7,97
35. Jarrad, A.M.; Karoli, T.; Blaskovich, M.A.; Lyras, D.; Cooper, M.A. Clostridium difficile drug pipeline:
Challenges in discovery and development of new agents. J. Med. Chem. 2015, 58, 5164–5185. [CrossRef]
[PubMed]
36. Lessa, F.C.; Mu, Y.; Bamberg, W.M.; Beldavs, Z.G.; Dumyati, G.K.; Dunn, J.R.; Farley, M.M.; Holzbauer, S.M.;
Meek, J.I.; Phipps, E.C.; et al. Burden of Clostridium difficile infection in the United States. N. Engl. J. Med.
2015, 372, 825–834. [CrossRef]
37. Dubberke, E.R.; Olsen, M.A. Burden of Clostridium difficile on the healthcare system. Clin. Infect. Dis. 2012,
55, S88–S92. [CrossRef]
38. Dawson, L.F.; Valiente, E.; Faulds-Pain, A.; Donahue, E.H.; Wren, B.W. Characterisation of Clostridium difficile
biofilm formation, a role for Spo0A. PLoS ONE 2012, 7, e50527. [CrossRef]
39. Dhapa, T.; Leuzzi, R.; Ng, Y.K.; Baban, S.T.; Adamo, R.; Kuehne, S.A.; Scarselli, M.; Minton, N.P.; Serruto, D.;
Unnikrishnan, M. Multiple factors modulate biofilm formation by the anaerobic pathogen Clostridium difficile.
J. Bacteriol. 2013, 195, 545–555.
40. Donelli, G.; Vuotto, C.; Cardines, R.; Mastrantonio, P. Biofilm-growing intestinal anaerobic bacteria.
FEMS Immunol. Med. Microbiol. 2012, 65, 318–325. [CrossRef]
41. Semenyuk, E.G.; Laning, M.L.; Foley, J.; Johnston, P.F.; Knight, K.L.; Gerding, D.N.; Driks, A. Spore formation
and toxin production in Clostridium difficile biofilms. PLoS ONE 2014, 9, e87757. [CrossRef][PubMed]
42. Swidsinski, A.; Weber, J.; Loening-Baucke, V.; Hale, L.P.; Lochs, H. Spatial organization and composition
of the mucosal flora in patients with inflammatory bowel disease. J. Clin. Microbiol. 2005, 43, 3380–3389.
[CrossRef][PubMed]
43. Macfarlane, S.; Dillon, J. Microbial biofilms in the human gastrointestinal tract. J. Appl. Microbiol. 2007,
102, 1187–1196. [CrossRef][PubMed]
44. Costerton, J.W.; Stewart, P.S.; Greenberg, E.P. Bacterial biofilms: A common cause of persistent infections.
Science 1999, 284, 1318–1322. [CrossRef][PubMed]
45. Anderl, J.N.; Franklin, M.J.; Stewart, P.S. Role of antibiotic penetration limitation in Klebsiella pneumoniae
biofilm resistance to ampicillin and ciprofloxacin. Antimicrob. Agents Chemother. 2000, 44, 1818–1824.
[CrossRef][PubMed]
46. Stewart, P.S.; Costerton, J.W. Antibiotic resistance of bacteria in biofilms. Lancet 2001, 358, 135–138. [CrossRef]
47. Stewart, P.S. Mechanisms of antibiotic resistance in bacterial biofilms. Int. J. Med. Microbiol. 2002, 292, 107–113.
[CrossRef][PubMed]
48. Zuroff, T.R.; Bernstein, H.; Lloyd-Randolfi, J.; Jimenez-Taracido, L.; Stewart, P.S.; Carlson, R.P. Robustness
analysis of culturing perturbations on Escherichia coli colony biofilm beta-lactam and aminoglycoside
antibiotic tolerance. BMC Microbiol. 2010, 10, 185. [CrossRef][PubMed]
49. Shreiner, A.B.; Kao, J.Y.; Young, V.B. The gut microbiome in health and in disease. Curr. Opin. Gastroenterol.
2015, 31, 69. [CrossRef][PubMed]
50. Henson, M.A.; Phalak, P. Byproduct Cross Feeding and Community Stability in an In Silico Biofilm Model
of the Gut Microbiome. Processes 2017, 5, 13. [CrossRef]
51. Henson, M.A.; Phalak, P. Microbiota dysbiosis in inflammatory bowel diseases: in silico investigation of the
oxygen hypothesis. BMC Syst. Biol. 2017, 11, 145. [CrossRef][PubMed]
52. Rivière, A.; Selak, M.; Lantin, D.; Leroy, F.; De Vuyst, L. Bifidobacteria and butyrate-producing colon bacteria:
Importance and strategies for their stimulation in the human gut. Front. Microbiol. 2016, 7, 979. [CrossRef]
[PubMed]
53. Ríos-Covián, D.; Ruas-Madiedo, P.; Margolles, A.; Gueimonde, M.; de los Reyes-Gavilán, C.G.; Salazar, N.
Intestinal short chain fatty acids and their link with diet and human health. Front. Microbiol. 2016, 7, 185.
[CrossRef][PubMed]
54. Jakobsdottir, G.; Xu, J.; Molin, G.; Ahrne, S.; Nyman, M. High-fat diet reduces the formation of butyrate,
but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these
effects. PLoS ONE 2013, 8, e80476. [CrossRef][PubMed]
55. Ferreyra, J.A.; Wu, K.J.; Hryckowian, A.J.; Bouley, D.M.; Weimer, B.C.; Sonnenburg, J.L. Gut microbiotaproduced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host
Microbe 2014, 16, 770–777. [CrossRef][PubMed]
56. Köpke, M.; Straub, M.; Dürre, P. Clostridium difficile is an autotrophic bacterial pathogen. PLoS ONE 2013,
8, e62157. [CrossRef][PubMed]
37
35. Jarrad, A.M.; Karoli, T.; Blaskovich, M.A.; Lyras, D.; Cooper, M.A. Clostridium difficile drug pipeline:
Challenges in discovery and development of new agents. J. Med. Chem. 2015, 58, 5164–5185. [CrossRef]
[PubMed]
36. Lessa, F.C.; Mu, Y.; Bamberg, W.M.; Beldavs, Z.G.; Dumyati, G.K.; Dunn, J.R.; Farley, M.M.; Holzbauer, S.M.;
Meek, J.I.; Phipps, E.C.; et al. Burden of Clostridium difficile infection in the United States. N. Engl. J. Med.
2015, 372, 825–834. [CrossRef]
37. Dubberke, E.R.; Olsen, M.A. Burden of Clostridium difficile on the healthcare system. Clin. Infect. Dis. 2012,
55, S88–S92. [CrossRef]
38. Dawson, L.F.; Valiente, E.; Faulds-Pain, A.; Donahue, E.H.; Wren, B.W. Characterisation of Clostridium difficile
biofilm formation, a role for Spo0A. PLoS ONE 2012, 7, e50527. [CrossRef]
39. Dhapa, T.; Leuzzi, R.; Ng, Y.K.; Baban, S.T.; Adamo, R.; Kuehne, S.A.; Scarselli, M.; Minton, N.P.; Serruto, D.;
Unnikrishnan, M. Multiple factors modulate biofilm formation by the anaerobic pathogen Clostridium difficile.
J. Bacteriol. 2013, 195, 545–555.
40. Donelli, G.; Vuotto, C.; Cardines, R.; Mastrantonio, P. Biofilm-growing intestinal anaerobic bacteria.
FEMS Immunol. Med. Microbiol. 2012, 65, 318–325. [CrossRef]
41. Semenyuk, E.G.; Laning, M.L.; Foley, J.; Johnston, P.F.; Knight, K.L.; Gerding, D.N.; Driks, A. Spore formation
and toxin production in Clostridium difficile biofilms. PLoS ONE 2014, 9, e87757. [CrossRef][PubMed]
42. Swidsinski, A.; Weber, J.; Loening-Baucke, V.; Hale, L.P.; Lochs, H. Spatial organization and composition
of the mucosal flora in patients with inflammatory bowel disease. J. Clin. Microbiol. 2005, 43, 3380–3389.
[CrossRef][PubMed]
43. Macfarlane, S.; Dillon, J. Microbial biofilms in the human gastrointestinal tract. J. Appl. Microbiol. 2007,
102, 1187–1196. [CrossRef][PubMed]
44. Costerton, J.W.; Stewart, P.S.; Greenberg, E.P. Bacterial biofilms: A common cause of persistent infections.
Science 1999, 284, 1318–1322. [CrossRef][PubMed]
45. Anderl, J.N.; Franklin, M.J.; Stewart, P.S. Role of antibiotic penetration limitation in Klebsiella pneumoniae
biofilm resistance to ampicillin and ciprofloxacin. Antimicrob. Agents Chemother. 2000, 44, 1818–1824.
[CrossRef][PubMed]
46. Stewart, P.S.; Costerton, J.W. Antibiotic resistance of bacteria in biofilms. Lancet 2001, 358, 135–138. [CrossRef]
47. Stewart, P.S. Mechanisms of antibiotic resistance in bacterial biofilms. Int. J. Med. Microbiol. 2002, 292, 107–113.
[CrossRef][PubMed]
48. Zuroff, T.R.; Bernstein, H.; Lloyd-Randolfi, J.; Jimenez-Taracido, L.; Stewart, P.S.; Carlson, R.P. Robustness
analysis of culturing perturbations on Escherichia coli colony biofilm beta-lactam and aminoglycoside
antibiotic tolerance. BMC Microbiol. 2010, 10, 185. [CrossRef][PubMed]
49. Shreiner, A.B.; Kao, J.Y.; Young, V.B. The gut microbiome in health and in disease. Curr. Opin. Gastroenterol.
2015, 31, 69. [CrossRef][PubMed]
50. Henson, M.A.; Phalak, P. Byproduct Cross Feeding and Community Stability in an In Silico Biofilm Model
of the Gut Microbiome. Processes 2017, 5, 13. [CrossRef]
51. Henson, M.A.; Phalak, P. Microbiota dysbiosis in inflammatory bowel diseases: in silico investigation of the
oxygen hypothesis. BMC Syst. Biol. 2017, 11, 145. [CrossRef][PubMed]
52. Rivière, A.; Selak, M.; Lantin, D.; Leroy, F.; De Vuyst, L. Bifidobacteria and butyrate-producing colon bacteria:
Importance and strategies for their stimulation in the human gut. Front. Microbiol. 2016, 7, 979. [CrossRef]
[PubMed]
53. Ríos-Covián, D.; Ruas-Madiedo, P.; Margolles, A.; Gueimonde, M.; de los Reyes-Gavilán, C.G.; Salazar, N.
Intestinal short chain fatty acids and their link with diet and human health. Front. Microbiol. 2016, 7, 185.
[CrossRef][PubMed]
54. Jakobsdottir, G.; Xu, J.; Molin, G.; Ahrne, S.; Nyman, M. High-fat diet reduces the formation of butyrate,
but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these
effects. PLoS ONE 2013, 8, e80476. [CrossRef][PubMed]
55. Ferreyra, J.A.; Wu, K.J.; Hryckowian, A.J.; Bouley, D.M.; Weimer, B.C.; Sonnenburg, J.L. Gut microbiotaproduced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host
Microbe 2014, 16, 770–777. [CrossRef][PubMed]
56. Köpke, M.; Straub, M.; Dürre, P. Clostridium difficile is an autotrophic bacterial pathogen. PLoS ONE 2013,
8, e62157. [CrossRef][PubMed]
37