the success of this therapy is evident between 19401970 , where twenty novel classes of antibiotics were discovered . these antibiotics vary , concerning their structure and mechanism of action . today , many of these drugs are not so effective because bacteria develop resistance , revealing a major challenge for our society . these proteins cleave the antibiotic , so it can not reach and interact with its target site . this is seen in streptococcus pneumonia   and is possible because the bacteria obtains dna from other bacteria via recombinational events . the third way resistance to antibiotics occurs is by targeting new sites , e.g. , methicillin - resistant staphylococcus aureus ( mrsa ) . instead of just relying on the original penicillin binding proteins to maintain bacterial membrane integrity , this strain of bacteria obtained dna from an unknown bacterial donor . it has a new gene called meca which codes for an alternative protein , called penicillin - binding protein 2a ( pbp2a ) . beta - lactam antibiotics are not capable of targeting these alternative proteins and thus , mrsa infections can be lethal . the last method involves a decreased uptake of the antibiotic , and if it does get into the cell , it is pumped out at a faster rate . these types of resistance are now prevailing in many species and strains of bacteria , in part , because of our propensity to use these agents too frequently . in time , bacteria with these resistant processes will emerge as the predominant form of the bacteria and will be difficult to kill . as we respond to these bacterial survival mechanisms we also inadvertently create drugs , which have the potential to influence other processes , e.g. , human behavior . this occurs because our drug discovery process fine tunes itself as resistance develops and we simultaneously develop stereo specific overlaps with naturally occurring biochemicals , altering their actions downstream . in addition to the above concerns in antibiotic development , many of the agents exhibit toxic effects on the host . in part , we surmise , this is due to unique evolutionary relationships that link selective biochemical and molecular aspects of mitochondrial biology to primordial processes in bacterial progenitors . the mitochondrion is an enslaved bacterium , normally producing significant amounts of atp in comparison to glycolysis . it has a similar structure and function to that found in bacteria , and it has a higher level of mutations compared to the nuclear rrna . antibiotics that are supposed to target pathogens will also bind to mitochondria with high affinity and cause side effects . the commonality of these antibiotic - induced side - effects lead physicians to create a term for this phenomenon called antimicrobial - induced mania , or antibiomania , since it can occur in neural tissues due to higher metabolic rates [ 1921 ] . we and others propose that mitochondria dysfunction may be part of the core problem for abnormal behaviors induced by antibiotic treatment , e.g. , depression , autism , etc . [ dysfunctional mitochondria have recently become a center of interest in explaining mental disorders [ 2833 ] . ciprofloxacin induces a small percent of treated patients to develop psychosis [ 3436 ] . in this regard , gamma - aminobutyric acid ( gaba ) receptor binding is inhibited by ciprofloxacin . importantly , the 18 kda translocator protein ( tspo ) localized to the outer mitochondrial membrane , previously designated as the peripheral - type benzodiazepine receptor , has been found to be temporally enhanced in the striatum and substantial nigra pars compacta in a neuro - inflammatory rat model of parkinson s disease   or diffuse nerve injury . interestingly , a reversal of repeated social stress - induced anxiety - like behavioral outcomes in rodents has been linked to the off - target peripheral effects of the widely used benzodiazepine lorazepam on tspo activation . more precisely , in vivo positron emission tomography ( pet ) scanning using the tspo - specific ligand [ c]dpa713 has demonstrated enhanced signal in select brain areas due to in vivo microglial activation as a result of aging and neuronal degeneration . interestingly , a subtype a of gaba receptor ( gabaa ) is regulated by the level of mitochondrial reactive oxygen species(mros ) at inhibitory synapses of cerebellar stellate cells . behavioral changes are not limited just to ciprofloxacin , but also occurs with exposure to metronidazole , ofloxacin , trimethoprim - sulfamethoxazole , cotrimoxazole , procaine penicillin and clarithromycin . additional examples of mitochondrial dysfunction , which are antibiotic - induced , are extensive and not limited to psychiatric behavior . aminoglycosides have been used for decades , and they are still considered to be effective for treating bacterial infections . however , there is a high risk of damage to sensory cells inside the inner ear when exposed to this antibiotic due to reactive oxygen species ( ros ) being released from the mitochondria [ 15,5155 ] . another experiment demonstrated that binding of aminoglycosides to the human mitochondrial h69 hairpin is the most likely factor in causing the side effect . moreover , tetracycline   also works by manipulating gene expression via the tet - on / tet - off system . in addition to gene manipulation , it will also induce unnecessary stress upon the mitochondria by disrupting translation . therefore , translation - targeted antibiotics must be used with extreme caution , especially in patients that have mitochondrial translation defects . antibiotic - induced mitochondrial damage can be pronounced on neurons , as noted earlier for behavior , especially given their metabolism , which requires 20% of the oxygen entering the body . this phenomenon suggests that aspects of antibiotic activity and cancers may be connected via energy processing . examples are erythromycin , tetracycline , and glycylcyclines , which have beneficial roles in eradicating some cancer stem cell lines while chloramphenicol , a broad spectrum antibiotic , exhibits conflicting results . this drug works through the jnk and pi3k pathways , which lead to a phosphorylated c - jun protein binding to the promoter region of the matrix metalloproteinase-13 region ( mm-13 ) . vancomycin is a very potent antibiotic and is prescribed against resistant staphylococcus aureus ( mrsa ) infections . hmox1 , a gene that is associated with cellular oxidative damage is regulated upon vancomycin exposure . exacerbating this event is the fact that antioxidant genes are down regulated , indicating that this potent drug could be increasing oxidative stress in nephrons . despite the danger in administering this antibiotic to kill staphylococcus aureus , the benefit of this drug clearly outweighs the risk of damages that can occur . the long - term effect of this agent on mitochondria has yet to be determined . pseudomonas aeruginosa destroys the cell by releasing pyocyanin , a permeable pigment that targets the mitochondrial respiratory chain . activation of the sphingomyelinase acid and the release of cytochrome c from the mitochondria shortly follow . staphylococcus , on the other hand , secretes a toxin ( pvl ) that creates holes in the mitochondrial outer membrane of neutrophils and stimulates apoptosis via bax genes . the prokaryotic bacterial organism has evolved , over millions of years , the ability to subvert the innate immune response via mitochondrial processes . this strategy , in all probability , is based on conserved common molecular knowledge . clearly , a good part of the communication is within and external to the cell s organelles , whether it is the eukaryotic mitochondria or prokaryotic ribosomes , this occurs via conformational matching , providing the reason for the mechanism of action . antibiotics can bind to the bacteria cell and cause changes in the bacterial physiological responses , and the efficacy of these antibiotics is limited or enhanced by environmental factors . the relationship that exists between antibiotics and induced ros have been studied through biochemical , biophysical and enzymatic assays . to further prove that ros , e.g. , h202 , is being produced , the promoters for oxidative stress regulator were analyzed and showed that there was significant activation of these genes due to the treatment of norfloxacin and ampicillin . these results prove extensive ros production is stimulated by antibiotics and strongly suggest that mitochondria , in general , can be involved in the response . the action of bactericidal drugs can be via interfering with the tricarboxylic acid cycle , destabilizing iron - sulfur clusters , so that iron will participate in the fenton reaction that occurs in the mitochondria , producing harmful hydroxyl radicals . hydroxyl radicals from the fenton reaction also will damage nucleotides in bacteria   and cause the mitochondria to undergo metabolic stress . a possible alternative to advance future antibiotic development involves targeting fatty acid biosynthesis because of differences found in eukaryotic and prokaryotic cells [ 8486 ] . key proteins that can be inhibited in bacteria are , for example , acps , accbcd , fabd , and coaa . these proteins assist in enzymatic activities in simple prokaryotes and inhibit fatty acid synthesis gene expression . platensimycin , platencin , and phomallenic acid   appear to destroy gram - positive cocci , such as staphylococcus- aureus , -pneumonia , and enterococcus faecium . relatively recent work demonstrates that some gram - positive bacteria are resistant to agents targeting fatty acid synthesis pathways . problematically , studies show that certain bacterial strains grow better when they get an exogenous source of fatty acids . interestingly , the large microbe population in the enteric system has not been examined for this phenomenon . these microbes may affect the activation state of white blood cells , which can enter the brain compartment and communicate with neurons . since these agents are already in use , their approval status for fda evaluation can be either shortened or exempt . in this case this timely mini - review brings attention to the role that mitochondria play in establishing an environment for normal overall behavior to emerge . pathological perturbations of this process via antibiotics , demonstrate the role this enslaved bacterium performs . a large amount of oxygen consumed , e.g. , in the brain , testifies to its moment by moment critical activity . in the shared commonality of chemical communication with bacteria , antibiotic - induced mitochondrial interactions represent a critical factor in micro - environmental and organismic survival . thus , an enhanced microbial presence or antibiotic level may alter the energy supply of a cell and thus enhance the occurrence of an induced behavior disorder . in this case , the potential to initiate mitochondrial dysfunction becomes clear , and this cascading type of action ends in stimulating abnormal behaviors . clearly , antibiotics have an important place in medicine ; despite the risk of damage to the host . in this scenario , one may expect alterations in behavior since they will emerge from high - level energy nerve cells . we speculate that in susceptible individuals and ones using these agents for extended periods of time and non - recommended doses , antibiotics may turn an acute stress response into one that is chronic .
clinical usage of several classes of antibiotics is associated with moderate to severe side effects due to the promotion of mitochondrial dysfunction . 
 we contend that this may be due to perturbation of unique evolutionary relationships that link selective biochemical and molecular aspects of mitochondrial biology to conserved enzymatic processes derived from bacterial progenitors . 
 operationally , stereo - selective conformational matching between mitochondrial respiratory complexes , cytosolic and nuclear signaling complexes appears to support the conservation of a critically important set of chemical messengers required for existential regulation of homeostatic cellular processes . 
 accordingly , perturbation of normative mitochondrial function by select classes of antibiotics is certainly reflective of the high degree of evolutionary pressure designed to maintain ongoing bidirectional signaling processes between cellular compartments . 
 these issues are of critical importance in evaluating potentially severe side effects of antibiotics on complex behavioral functions mediated by cns neuronal groups . 
 the cns is extremely dependent on delivery of molecular oxygen for maintaining a required level of metabolic activity , as reflected by the high concentration of neuronal mitochondria . 
 thus , it is not surprising to find several distinct behavioral abnormalities conforming to established psychiatric criteria that are associated with antibiotic usage in humans 
 . the manifestation of acute and/or chronic psychiatric conditions following antibiotic usage may provide unique insights into key etiological factors of major psychiatric syndromes that involve rundown of cellular bioenergetics via mitochondrial dysfunction . 
 thus , a potential window of opportunity exists for development of novel therapeutic agents targeting diminished mitochondrial function as a factor in severe behavioral disorders .